EP2 Receptor Agonists

ABSTRACT

The disclosure provides EP2 receptor agonist compounds and methods for using the compounds for treating conditions which can be alleviated by agonism of an EP2 receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 12/346,516,filed Dec. 30, 2008, which is a divisional of application Ser. No.11/950,613, filed Dec. 5, 2007, now U.S. Pat. No. 7,662,839 whichapplication is a divisional of application Ser. No. 11/055,724, filedFeb. 11, 2005, now U.S. Pat. No. 7,326,732, which claims benefit of U.S.Provisional Application Nos. 60/626,940, filed Nov. 12, 2004, and60/543,538, filed Feb. 12, 2004; the entire contents of each which arehereby incorporated by reference in this application.

This invention relates to EP₂ receptor agonists, pharmaceuticalcompositions comprising such compounds, and the use of such compoundsand compositions to treat various diseases.

BACKGROUND TO THE INVENTION

Prostanoids comprise prostaglandins (PGs) and thromboxanes (Txs) andtheir receptors fall into five different classes (DP, EP, FP, IP and TP)based on their sensitivity to the five naturally occurring prostanoids,PGD₂, PGE₂, PGF_(2α), PGI₂ and TxA₂, respectively (Coleman, R. A.,Prostanoid Receptors. IUPHAR compendium of receptor characterisation andclassification, 2^(nd) edition, 338-353, ISBN 0-9533510-3-3, 2000). EPreceptors (for which the endogenous ligand is PGE₂) have been subdividedinto four types termed EP₁, EP₂, EP₃ and EP₄. These four types of EPreceptors have been cloned and are distinct at both a molecular andpharmacological level (Coleman, R. A., 2000)

EP₂ agonists have been shown to be effective in the treatment of anumber of conditions, including (but not limited to) dysmenorrhoea (WO03/037433), pre-term labour (GB 2 293 101), glaucoma (WO 03/040126),ocular hypertension (WO 03/040126), immune disorders (Nataraj, C., etal., J. Clin. Invest., 108, 1229-1235 (2001)), osteoporosis (WO98/27976, WO 01/46140), asthma (Tilley, et al., Am. J. Physiol. LungCell Mol. Physiol., 284, L599-606 (2003)), allergy, bone disease (WO02/24647), fracture repair (WO 98/27976, WO 02/24647), male sexualdysfunction (WO 00/40248), female sexual dysfunction (U.S. Pat. No.6,562,868), periodontal disease (WO 00/31084), gastric ulcer (U.S. Pat.No. 5,576,347) and renal disease (WO 98/34916).

In co-pending applications GB 0329620.9, filed 22 Dec. 2003 and acorresponding US provisional application filed 24 Dec. 2003, which arehereby incorporated by reference, it has been shown that EP₂ agonistsinhibit lymphocyte activation and the release of pro-inflammatorycytokines from alveolar macrophages. In addition, EP₂ activationinhibits monocyte and neutrophil activation. Thus, EP₂ agonists shouldprove useful in the treatment of inflammatory and immune disorders suchas psoriasis, dermatitis, rheumatoid arthritis, multiple sclerosis,scleroderma, transplant rejection, allergy, systemic lupuserythematosus, vasculitis, type 1 diabetes mellitus, and inflammatorylung diseases such as chronic obstructive pulmonary disease, asthma,acute respiratory distress syndrome and cystic fibrosis.

In addition, EP₂ agonists can also be used in the treatment of fibrosis,including, but not limited to idiopathic pulmonary fibrosis, sclerodermaand systemic sclerosis, post-operative fibrosis following trabulectomy,liver repair and regeneration following cirrhosis, hepatitis, toxicity,cancer or renal fibrosis. EP₂ agonists can also be used in theprevention of fibroblast to myofibroblast conversion to treat asthma andother fibrotic lung diseases. EP₂ agonists may also be used to maintainductus arteriosus patency in infants with congenital heart disease.

Compounds which combine EP₂ receptor agonist and EP, receptor antagonistproperties may prove useful in the treatment of several diseasesincluding myometrial disorders, bone diseases including osteoporosis andosteoarthritis, allergic and immune disorders such as psoriasis,transplant rejection, and asthma, inflammatory diseases such asrheumatoid arthritis, chronic obstructive pulmonary disease and acuterespiratory disease syndrome, and fibrotic lung diseases.

SUMMARY OF THE INVENTION

A first aspect of the present invention provides a compound of formula(I):

or a salt, solvate and chemically protected form thereof, wherein:R⁵ is an optionally substituted C₅₋₂₀ aryl or C₄₋₂₀ alkyl group;A is selected from the group consisting of:

wherein X and Y are selected from the group consisting of: O and CR³; Sand CR³; NH and CR³; NH and N; O and N; S and N; N and S; and N and O,and where the dotted lines indicate a double bond in the appropriatelocation, and where Q is either N or CH;R³ is selected from H, F, Cl and optionally substituted C₁₋₄ alkyl, C₁₋₄alkoxy, C₅₋₇ aryl and C₅₋₇ aryl-C₁₋₄ alkyl groups;R⁴ is selected from H, F, Cl and optionally substituted C₁₋₄ alkyl, C₁₋₄alkoxy, C₅₋₇ aryl and C₅₋₇ aryl-C₁₋₄ alkyl groups;R⁶ is selected from H, F, Cl and optionally substituted C₁₋₄ alkyl, C₁₋₄alkoxy, C₅₋₇ aryl and C₅₋₇ aryl-C₁₋₄ alkyl groups;D is selected from:

B is selected from the group consisting of:

where R^(N′) is selected from H and C₁₋₄ alkyl;where one of R^(P3) and R^(P4) is —C_(m) alkylene-R² and the other ofR^(P3) and R^(P4) is H, m and n can be 0 or 1, and m+n=1 or 2; andadditionally when R^(P3) is —C_(m) alkylene-R², m can also be 2 or 3,and m+n=1, 2, 3 or 4, and when R² is tetrazol-5-yl, m+n may be 0; orwhere one of R^(P3) and R^(P4) is —O—CH₂—R², and the other of R^(P3) andR^(P4) is H, n is 0;R^(N) is H or optionally substituted C₁₋₄ alkyl;R² is either:(i) —CO₂H (carboxy);

(ii) —CONH₂;

(iii) —CH₂—OH (methoxy); or(iv) tetrazol-5-yl.

Therefore, A may be one of the following groups:

A second aspect of the present invention provides a compound of formula(I) or a pharmaceutically acceptable salt thereof for use in a method oftherapy.

A third aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) as defined in the firstaspect or a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.

A fourth aspect of the present invention provides the use of a compoundof formula (I) or a pharmaceutically acceptable salt thereof in thepreparation of a medicament for the treatment of a condition alleviatedby agonism of an EP₂ receptor.

A fifth aspect of the present invention provides a method of treating acondition which can be alleviated by agonism of an EP₂ receptor, whichmethod comprises administering to a patient in need of treatment aneffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof.

In the fourth and fifth aspects of the invention, the agonism of the EP₂receptor may be selective, or may be accompanied by antagonism of theEP₄ receptor.

Conditions which can be alleviated by agonism of an EP₂ receptor arediscussed above, and particularly include dysmenorrhoea, pre-termlabour, glaucoma, ocular hypertension, immune disorders, inflammatorydisorders, osteoporosis, asthma, chronic obstructive pulmonary disease,allergy, bone disease, fracture repair, male sexual dysfunction, femalesexual dysfunction, infertility, periodontal disease, gastric ulcer,renal disease and psoriasis.

Conditions which can be alleviated by combined agonism of EP₂ receptorsand antagonism of EP, receptors are discussed above, and particularlyinclude myometrial disorders, bone diseases including osteoporosis andosteoarthritis, allergic and immune disorders such as psoriasis,transplant rejection, and asthma, inflammatory diseases such asrheumatoid arthritis, chronic obstructive pulmonary disease and acuterespiratory disease syndrome, and fibrotic lung diseases.

EP receptor agonists are known to be able to inhibit T-cell activationand the release of pro-inflammatory cytokines, although the EP receptorinvolved in mediating these effects in human T-cells has not beenpreviously defined. Some of the present inventors have discovered thatEP₂ agonists inhibit human T-cell activation (proliferation) and inhibitthe release of multiple pro-inflammatory cytokines including interleukin2 (IL-2) tumour necrosis factor (TNF_(α)) and interferon gamma (IFNγ),as described in co-pending US and International applications entitled“EP₂ Agonists” filed 22 Dec. 2004 in the name of Borman, R. A. et al.,(PCT/GB2004/005421), which are herein incorporated by reference. Thisprofile of activity strongly suggests that EP₂ receptor agonists will beuseful in treating immune and inflammatory disorders, including but notlimited to psoriasis, psoriatic arthritis, dermatitis, rheumatoidarthritis, transplant rejection, inflammatory bowel disease, systemiclupus erythematosus, Graves' disease, scleroderma, multiple sclerosis,Type I diabetes, and transplant rejection, and in particular psoriasis(Griffiths, C., Current Drugs Targets—Inflammation & Allergy, 3,157-161, (2004); Lebwohl, M., Lancet, 361, 1197-1204 (2003); Salim, A. &Emerson, R., Curr. Opin. Investig. Drugs, 2(11), 1546-8 (2001)).Therefore, a further condition which can be alleviated by agonism of anEP₂ receptor is psoriasis.

Furthermore, some of the present inventors have also shown that EP₂receptor agonists inhibit the release of the pro-inflammatory cytokine,TNF_(α) from human monocytes and alveolar macrophages, as described inco-pending US and International applications entitled “EP₂ Agonists”filed 22 Dec. 2004 in the name of Borman, R. A. et al.,(PCT/GB2004/005421), which are herein incorporated by reference. Thisprofile of activity adds further evidence to the view that that EP₂receptor agonists will be useful in treating immune and inflammatorydisorders and in particular, inflammatory lung diseases (including, butnot limited to: asthma, chronic obstructive pulmonary disease, acuterespiratory distress syndrome, pulmonary fibrosis and cystic fibrosis).

Furthermore, aspects of the present invention relate to the use of EP₂agonists to treat conditions ameliorated by the inhibition of IL-2TNF_(α) and/or IFNγ production and the use of an EP₂ agonist in thepreparation of a medicament for the treatment of a condition alleviatedby inhibition of IL-2 production.

The present invention also provides methods of stimulating EP₂ receptorsand/or inhibiting the production of IL-2, TNF_(α) and/or IFNγ, in vitroor in vivo, comprising contacting a cell with an effective amount of acompound of the first aspect of the present invention.

Compounds of the present invention can be assayed to determine whetherthey act as antagonists of an EP, receptor. Suitable assay methods aredescribed in example 6 below.

The present invention also provides methods of agonising EP₂, andpossible antagonizing EP₄ receptors, in vitro or in vivo, comprisingcontacting a cell with an effective amount of a compound of formula (I).

In some embodiments, the compounds described above which function as EP₂agonists may be selective as against modulation of one or more of theother three EP receptors, i.e. EP₁, EP₃ and EP₄. This selectivity allowsfor targeting of the effect of the compounds of the invention, withpossible benefits in the treatment of certain conditions.

DEFINITIONS Monodentate Groups

(I.e Groups with One Point of Covalent Attachment)

Alkyl: The term “alkyl” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from a carbon atom of a hydrocarboncompound having from 1 to 20 carbon atoms (unless otherwise specified),which may be aliphatic or alicyclic, and which may be saturated orunsaturated. Thus, the term “alkyl” includes the sub-classes alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cylcoalkynyl, etc., discussed below.

In the context of alkyl groups, the prefixes (e.g. C₁₋₄, C₁₋₇, C₁₋₂₀,C₂₋₇, C₃₋₇) denote the number of carbon atoms, or range of number ofcarbon atoms. For example, the term “C₁₋₄ alkyl” as used herein,pertains to an alkyl group having from 1 to 4 carbon atoms. Examples ofgroups of alkyl groups include C₁₋₄ alkyl (“lower alkyl”), C₁₋₇ alkyland C₄₋₂₀ alkyl. Note that the first prefix may vary according to otherlimitations; for example, for unsaturated alkyl groups, the first prefixmust be at least 2; for cyclic alkyl groups, the first prefix must be atleast 3; etc.

Examples of saturated alkyl groups include, but are not limited to,methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl (C₅), hexyl(C₆), heptyl (C₇), octyl (C₈), nonyl (C₉), decyl (C₁₀), undecyl (C₁₁),dodecyl (C₁₂), tridecyl (C₁₃), tetradecyl (C₁₄), pentadecyl (C₁₅), andeicodecyl (C₂₀).

Examples of saturated linear alkyl groups include, but are not limitedto, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl (C₄), n-pentyl(amyl) (C₅), n-hexyl (C₆), and n-heptyl (C₇).

Examples of saturated branched alkyl groups include iso-propyl (C₃),iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄), iso-pentyl (C₅), andneo-pentyl (C₅).

Alkenyl: The term “alkenyl” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon double bonds. Examples of alkenylgroups include C₂₋₄ alkenyl, C₂₋₇ alkenyl and C₂₋₂₀alkenyl. Examples ofalkenyl groups include, but are not limited to, ethenyl (vinyl,—CH═CH₂), 1-propenyl (—CH═CH—CH₃), 2-propenyl (allyl, —CH—CH═CH₂),isopropenyl (1-methylvinyl, —C(CH₃)═CH₂), butenyl (C₄), pentenyl (C₅),and hexenyl (C₆).

Alkynyl: The term “alkynyl” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon triple bonds. Examples of groups ofalkynyl groups include C₂₋₄ alkynyl, C₂₋₇ alkynyl and C₂₋₂₀ alkynyl.Examples of alkynyl groups include, but are not limited to, ethynyl(ethinyl, —C≡CH) and 2-propynyl (propargyl, —CH₂—C≡CH).

Cycloalkyl: The term “cycloalkyl” as used herein, pertains to an alkylgroup which is also a cyclyl group; that is, a monovalent moietyobtained by removing a hydrogen atom from an alicyclic ring atom of acarbocyclic ring of a carbocyclic compound, which carbocyclic ring maybe saturated or unsaturated, which moiety has from 3 to 7 carbon atoms(unless otherwise specified), including from 3 to 7 ring atoms. Thus,the term “cycloalkyl” includes the sub-classes cycloalkenyl andcycloalkynyl. Preferably, each ring has from 3 to 7 ring atoms. Examplesof groups of cycloalkyl groups include C₃₋₇ cycloalkyl.

Examples of cycloalkyl groups include, but are not limited to, thosederived from:

-   -   saturated monocyclic hydrocarbon compounds:        cyclopropane (C₃), cyclobutane (C₄), cyclopentane (C₅),        cyclohexane (C₆), cycloheptane (C₇), methylcyclopropane (C₄),        dimethylcyclopropane (C₅), methylcyclobutane (C₅),        dimethylcyclobutane (C₆), methylcyclopentane (C₆),        dimethylcyclopentane (C₇), methylcyclohexane (C₇)        dimethylcyclohexene (C₈), menthane (C₁₀);    -   unsaturated monocyclic hydrocarbon compounds:        cyclopropene (C₃), cyclobutene (C₄), cyclopentene (C₅),        cyclohexene (C₆), methylcyclopropene (C₄), dimethylcyclopropene        (C₅), methylcyclobutene (C₅), dimethylcyclobutene (C₆),        methylcyclopentene (C₆), dimethylcyclopentene (C₇),        methylcyclohexene (C₇) dimethylcyclohexene (C₈);    -   saturated polycyclic hydrocarbon compounds:        thujane (C₁₀), carane (C₁₀), pinane (C₁₀), bornane (C₁₀),        norcarane (C₇), norpinane (C₇), norbornane (C₇), adamantane        (C₁₀), decalin (decahydronaphthalene) (C₁₀);    -   unsaturated polycyclic hydrocarbon compounds:        camphene (C₁₀), limonene (C₁₀), pinene (C₁₀).

Heterocyclyl: The term “heterocyclyl” as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a ring atomof a heterocyclic compound, which moiety has from 3 to 20 ring atoms(unless otherwise specified), of which from 1 to 10 are ringheteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of whichfrom 1 to 4 are ring heteroatoms.

In this context, the prefixes (e.g. C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆ heterocyclyl” as usedherein, pertains to a heterocyclyl group having 5 or 6 ring atoms.Examples of groups of heterocyclyl groups include C₃₋₂₀ heterocyclyl,C₅₋₂₀ heterocyclyl, C₃₋₁₅ heterocyclyl, C₅₋₁₅ heterocyclyl, C₃₋₁₂heterocyclyl, C₅₋₁₂ heterocyclyl, C₃₋₁₀ heterocyclyl, C₅₋₁₀heterocyclyl, C₃₋₇ heterocyclyl, C₅₋₇ heterocyclyl, and C₅₋₆heterocyclyl.

Examples of monocyclic heterocyclyl groups include, but are not limitedto, those derived from:

N₁: aziridine (C₃), azetidine (C₄), pyrrolidine (tetrahydropyrrole)(C₅), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrroleor 3H-pyrrole (isopyrrole, isoazole) (C₅), piperidine (C₆),dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);O₁: oxirane (C₃), oxetane (C₄), oxolane (tetrahydrofuran) (C₅), oxole(dihydrofuran) (C₅), oxane (tetrahydropyran) (C₆), dihydropyran (C₆),pyran (C₆), oxepin (C₇);S₁: thiirane (C₃), thietane (C₄), thiolane (tetrahydrothiophene) (C₅),thiane (tetrahydrothiopyran) (C₆), thiepane (C₇);O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);O₃: trioxane (C₆);N₂: imidazolidine (C₅), pyrazolidine (diazolidine) (C₅), imidazoline(C₅), pyrazoline (dihydropyrazole) (C₅), piperazine (C₆);N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅), tetrahydroisoxazole(C₅), dihydroisoxazole (C₅), morpholine (C₆), tetrahydrooxazine (C₆),dihydrooxazine (C₆), oxazine (C₆);N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);N₂O₁: oxadiazine (C₆);O₁S₁: oxathiole (C₅) and oxathiane (thioxane) (C₆); and,N₁O₁S₁: oxathiazine (C₆).

Aryl: The term “aryl” as used herein, pertains to a monovalent moietyobtained by removing a hydrogen atom from an aromatic ring atom of anaromatic compound, which moiety has from 3 to 20 ring atoms (unlessotherwise specified). Preferably, each ring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g. C₃₋₂₀, C₅₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆ aryl” as used herein,pertains to an aryl group having 5 or 6 ring atoms. Examples of groupsof aryl groups include C₃₋₂₀ aryl, C₅₋₂₀ aryl, C₅₋₁₅ aryl, C₅₋₁₂ aryl,C₅₋₁₀ aryl, C₅₋₇ aryl, C₅₋₆ aryl, C₅ aryl, and C₆ aryl.

The ring atoms may be all carbon atoms, as in “carboaryl groups”.Examples of carboaryl groups include C₃₋₂₀ carboaryl, C₅₋₂₀ carboaryl,C₅₋₁₅ carboaryl, C₅₋₁₂ carboaryl, C₅₋₁₀ carboaryl, C₅₋₇ carboaryl, C₅₋₆carboaryl, C₅ carboaryl, and C₆ carboaryl.

Examples of carboaryl groups include, but are not limited to, thosederived from benzene (i.e. phenyl) (C₆), naphthalene (C₁₀), azulene(C₁₀), anthracene (C₁₄), phenanthrene (C₁₄), naphthacene (C₁₈), andpyrene (C₁₆).

Examples of aryl groups which comprise fused rings, at least one ofwhich is an aromatic ring, include, but are not limited to, groupsderived from indane (e.g., 2,3-dihydro-1H-indene) (C₉), indene (C₉),isoindene (C₉), tetraline (1,2,3,4-tetrahydronaphthalene (C₁₀),acenaphthene (C₁₂), fluorene (C₁₃), phenalene (C₁₃), acephenanthrene(C₁₅), and aceanthrene (C₁₆).

Alternatively, the ring atoms may include one or more heteroatoms, as in“heteroaryl groups”. Examples of heteroaryl groups include C₃₋₂₀heteroaryl, C₅₋₂₀ heteroaryl, C₅₋₁₅ heteroaryl, C₅₋₁₂ heteroaryl, C₅₋₁₀heteroaryl, C₅₋₇ heteroaryl, C₅₋₆ heteroaryl, C₅ heteroaryl, and C₆heteroaryl.

Examples of monocyclic heteroaryl groups include, but are not limitedto, those derived from:

N₁: pyrrole (azole) (C₅), pyridine (azine) (C₆);O₁: furan (oxole) (C₅);S₁: thiophene (thiole) (C₅);N₁O₁: oxazole (C₅), isoxazole (C₅), isoxazine (C₆);N₂O₁: oxadiazole (furazan) (C₅);N₃O₁: oxatriazole (C₅);N₁S₁: thiazole (C₅), isothiazole (C₅);N₂: imidazole (1,3-diazole) (C₅), pyrazole (1,2-diazole) (C₅),pyridazine (1,2-diazine) (C₆), pyrimidine (1,3-diazine) (C₆), pyrazine(1,4-diazine) (C₆);N₃: triazole (C₅), triazine (C₆); and,N₄: tetrazole (C₅).

Examples of heteroaryl groups which comprise fused rings, include, butare not limited to:

-   -   C₉ (with 2 fused rings) derived from benzofuran (O₁),        isobenzofuran (O₁), indole (N₁), isoindole (N₁), indolizine        (N₁), indoline (N₁), isoindoline (N₁), purine (N₄) (e.g.,        adenine, guanine), benzimidazole (N₂), indazole (N₂),        benzoxazole (N₁O₁), benzisoxazole (N₃O₁), benzodioxole (O₂),        benzofurazan (N₂O₁), benzotriazole (N₃), benzothiofuran (S₁),        benzothiazole (N₁S₂), benzothiadiazole (N₂S);    -   C₁₀ (with 2 fused rings) derived from chromene (O₂), isochromene        (O₁), chroman (O₁), isochroman (O₁), benzodioxan (O₂), quinoline        (N₁), isoquinoline (N₁), quinolizine (N₁), benzoxazine (N₁O₁),        benzodiazine (N₂), pyridopyridine (N₂), quinoxaline (N₂),        quinazoline (N₂), cinnoline (N₂), phthalazine (N₂),        naphthyridine (N₂), pteridine (N₄);    -   C₁₁ (with 2 fused rings) derived from benzodiazepine (N₂);    -   C₁₃ (with 3 fused rings) derived from carbazole (N₁),        dibenzofuran (O₁), dibenzothiophene (S₁), carboline (N₂),        perimidine (N₂), pyridoindole (N₂); and,    -   C₁₄ (with 3 fused rings) derived from acridine (N₁), xanthene        (O₁), thioxanthene (S₁), oxanthrene (O₂), phenoxathiin (O₁S₁),        phenazine (N₂), phenoxazine (N₂O₁), phenothiazine (N₁S₁),        thianthrene (S₂), phenanthridine (N₁), phenanthroline (N₂),        phenazine (N₂).

If a heteroaryl or heterocyclyl group contains a nitrogen ring atom,this ring atom, where possible, may be in a oxidised state, as anN-oxide.

The above groups, whether alone or part of another substituent, maythemselves optionally be substituted with one or more groups selectedfrom themselves, the additional monodentate substituents listed belowand alkoxylene.

Halo: —F, —Cl, —Br, and —I.

Hydroxy: —OH.

Ether: —OR, wherein R is an ether substituent, for example, a C₁₋₇ alkylgroup (also referred to as a C₁₋₇ alkoxy group, discussed below), aC₃₋₂₀ heterocyclyl group (also referred to as a C₃₋₂₀ heterocyclyloxygroup), or a C₅₋₂₀ aryl group (also referred to as a C₅₋₂₀ aryloxygroup), preferably a C₁₋₇ alkyl group.

C₁₋₇ alkoxy: —OR, wherein R is a C₁₋₇ alkyl group. Examples of C₁₋₇alkoxy groups include, but are not limited to, —OMe (methoxy), —OEt(ethoxy), —O(nPr) (n-propoxy), —O(iPr) (isopropoxy), —O(nBu) (n-butoxy),—O(sBu) (sec-butoxy), —O(iBu) (isobutoxy), and —O(tBu) (tert-butoxy).

Oxo (keto, -one): ═O.

Thione (thioketone): ═S.

Imino (imine): ═NR, wherein R is an imino substituent, for example,hydrogen, C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably hydrogen or a C₁₋₇ alkyl group. Examples of iminogroups include, but are not limited to, ═NH, ═NMe, ═NEt, and ═NPh.

Formyl (carbaldehyde, carboxaldehyde): —C(═O)H.

Acyl (keto): —C(═O)R, wherein R is an acyl substituent, for example, aC₁₋₇ alkyl group (also referred to as C₁₋₇ alkylacyl or C₁₋₇ alkanoyl),a C₃₋₂₀ heterocyclyl group (also referred to as C₃₋₂₀ heterocyclylacyl),or a C₅₋₂₀ aryl group (also referred to as C₅₋₂₀ arylacyl), preferably aC₁₋₇ alkyl group. Examples of acyl groups include, but are not limitedto, —C(═O)CH₃ (acetyl), —C(═O)CH₂CH₃ (propionyl), —C(═O)C(CH₃)₃(t-butyryl), and —C(═O)Ph (benzoyl, phenone).

Carboxy (carboxylic acid): —C(═O)OH.

Thiocarboxy (thiocarboxylic acid): —C(═S)SH.

Thiolocarboxy (thiolocarboxylic acid): —C(═O)SH.

Thionocarboxy (thionocarboxylic acid): —C(═S)OH.

Imidic acid: —C(═NH)OH.

Hydroxamic acid: —C(═NOH)OH.

Ester (carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR,wherein R is an ester substituent, for example, a C₁₋₇ alkyl group, aC₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkylgroup. Examples of ester groups include, but are not limited to,—C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh.

Acyloxy (reverse ester): —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Examples of acyloxy groupsinclude, but are not limited to, —OC(═O)CH₃ (acetoxy), —OC(═O)CH₂CH₃,—OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): —C(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of amido groups include, but are not limited to,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃, and—C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R², togetherwith the nitrogen atom to which they are attached, form a heterocyclicstructure as in, for example, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, and piperazinocarbonyl.

Acylamino: —NR¹C(═O)R², wherein R¹ is an amide substituent, for example,hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably hydrogen or a C₁₋₇ alkyl group, and R² is an acylsubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇ alkyl group.Examples of acylamide groups include, but are not limited to,—NHC(═O)CH₃, —NHC(═O)CH₂CH₃, and —NHC(═O)Ph. R¹ and R² may together forma cyclic structure, as in, for example, succinimidyl, maleimidyl, andphthalimidyl:

Thioamido (thiocarbamyl): —C(═S)NR¹R², wherein R¹ and R² areindependently amino substituents, as defined for amino groups. Examplesof thioamido groups include, but are not limited to, —C(═S)NH₂,—C(═S)NHCH₃, —C(═S)N(CH₃)₂, and —C(═S)NHCH₂CH₃.

Ureido: —N(R¹)CONR²R³ wherein R² and R³ are independently aminosubstituents, as defined for amino groups, and R¹ is a ureidosubstituent, for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀ aryl group, preferably hydrogen or a C₁₋₇alkyl group. Examples of ureido groups include, but are not limited to,—NHCONH₂, —NHCONHMe, —NHCONHEt, —NHCONMe₂, —NHCONEt₂, —NMeCONH₂,—NMeCONHMe, —NMeCONHEt, —NMeCONMe₂, and —NMeCONEt₂.

Guanidino: —NH—C(═NH)NH₂.

Tetrazolyl: a five membered aromatic ring having four nitrogen atoms andone carbon atom,

Amino: —NR¹R², wherein R¹ and R² are independently amino substituents,for example, hydrogen, a C₁₋₇ alkyl group (also referred to as C₁₋₇alkylamino or di-C₁₋₇ alkylamino), a C₃₋₂₀ heterocyclyl group, or aC₅₋₂₀aryl group, preferably H or a C₁₋₇ alkyl group, or, in the case ofa “cyclic” amino group, R¹ and R², taken together with the nitrogen atomto which they are attached, form a heterocyclic ring having from 4 to 8ring atoms. Amino groups may be primary (—NH₂), secondary (—NHR¹), ortertiary (—NHR¹R²), and in cationic form, may be quaternary (—⁺NR¹R²R³).Examples of amino groups include, but are not limited to, —NH₂, —NHCH₃,—NHC(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh. Examples of cyclic aminogroups include, but are not limited to, aziridino, azetidino,pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.

Amidine (amidino): —C(═NR)NR₂, wherein each R is an amidine substituent,for example, hydrogen, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group,or a C₅₋₂₀ aryl group, preferably H or a C₁₋₇ alkyl group. Examples ofamidine groups include, but are not limited to, —C(═NH)NH₂, —C(═NH)NMe₂,and —C(═NMe)NMe₂.

Nitro: —NO₂.

Nitroso: —NO.

Cyano (nitrile, carbonitrile): —CN.

Sulfhydryl (thiol, mercapto): —SH.

Thioether (sulfide): —SR, wherein R is a thioether substituent, forexample, a C₁₋₇ alkyl group (also referred to as a C₁₋₇ alkylthiogroup), a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group, preferably aC₁₋₇ alkyl group. Examples of C₁₋₇ alkylthio groups include, but are notlimited to, —SCH₃ and —SCH₂CH₃.

Disulfide: —SS—R, wherein R is a disulfide substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group (also referred to herein as C₁₋₇ alkyldisulfide). Examples of C₁₋₇ alkyl disulfide groups include, but are notlimited to, —SSCH₃ and —SSCH₂CH₃.

Sulfine (sulfinyl, sulfoxide): —S(═O)R, wherein R is a sulfinesubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples ofsulfine groups include, but are not limited to, —S(═O)CH₃ and—S(═O)CH₂CH₃.

Sulfone (sulfonyl): —S(═O)₂R, wherein R is a sulfone substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group, including, for example, afluorinated or perfluorinated C₁₋₇ alkyl group. Examples of sulfonegroups include, but are not limited to, —S(═O)₂CH₃ (methanesulfonyl,mesyl), —S(═O)₂CF₃ (triflyl), —S(═O)₂CH₂CH₃ (esyl), —S(═O)₂C₄F₉(nonaflyl), —S(═O)₂CH₂CF₃ (tresyl), —S(═O)₂CH₂CH₂NH₂ (tauryl), —S(═O)₂Ph(phenylsulfonyl, besyl), 4-methylphenylsulfonyl (tosyl),4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl (brosyl),4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and5-dimethylamino-naphthalen-1-ylsulfonate (dansyl).

Sulfinic acid (sulfino): —S(═O)OH, —SO₂H.

Sulfonic acid (sulfo): —S(═O)₂OH, —SO₃H.

Sulfinate (sulfinic acid ester): —S(═O)OR; wherein R is a sulfinatesubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclylgroup, or a C₅₋₂₀ aryl group, preferably a C₁₋₇ alkyl group. Examples ofsulfinate groups include, but are not limited to, —S(═O)OCH₃(methoxysulfinyl; methyl sulfinate) and —S(═O)OCH₂CH₃ (ethoxysulfinyl;ethyl sulfinate).

Sulfinyloxy: —OS(═O)R, wherein R is a sulfinyloxy substituent, forexample, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₇ alkyl group. Examples of sulfinyloxy groupsinclude, but are not limited to, —OS(═O)CH₃ and —OS(═O)CH₂CH₃.

Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide): —S(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of sulfamyl groups include, but are not limitedto, —S(═O)NH₂, —S(═O)NH(CH₃), —S(═O)N(CH₃)₂, —S(═O)NH(CH₂CH₃),—S(═O)N(CH₂CH₃)₂, and —S(═O)NHPh.

Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide):—S(═O)₂NR¹R², wherein R¹ and R² are independently amino substituents, asdefined for amino groups. Examples of sulfonamido groups include, butare not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂,—S(═O)₂NH(CH₂CH₃), —S(═O)₂N(CH₂CH₃)₂, and —S(═O)₂NHPh.

Sulfonamino: —NR¹S(═O)₂R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfonamino substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of sulfonamino groups include,but are not limited to, —NHS(═O)₂CH₃ and —N(CH₃)S(═O)₂C₆H₅.

Sulfinamino: —NR¹S(═O)R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfinamino substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀ aryl group,preferably a C₁₋₇ alkyl group. Examples of sulfinamino groups include,but are not limited to, —NHS(═O)CH₃ and —N(CH₃)S(═O)C₆H₅.

As already mentioned, the above described groups may be substituted, andparticular examples include, but are not limited to, C₃₋₂₀ aryl-C₁₋₇alkyl groups, which include benzyl (phenylmethyl, PhCH₂—), benzhydryl(Ph₂CH—), trityl (triphenylmethyl, Ph₃C—), phenethyl (phenylethyl,Ph-CH₂CH₂—), styryl (Ph-CH═CH—) and cinnamyl (Ph-CH═CH—CH₂—).

Bidentate Groups

(i.e. groups with two points of covalent attachment; linking groups)Alkylene: The term “C₁₋₃ alkylene”, as used herein, pertains to abidentate moiety obtained by removing two hydrogen atoms from each oftwo different carbon atoms, of a linear hydrocarbon compound having from1 to 3 carbon atoms, which may be saturated or unsaturated. Thus, theterm “alkylene” includes the sub-classes alkenylene and alkynylene.

In this context, the prefix C₁₋₃ denotes the number of carbon atoms, orrange of number of carbon atoms.

Examples of saturated C₁₋₃ alkylene groups include —CH₂— (methylene),—CH₂CH₂— (ethylene) and —CH₂CH₂CH₂— (propylene).

Examples of unsaturated C₁₋₃ alkylene groups (which may be termed “C₂₋₃alkenylene” or “C₂₋₃ alkynylene”, as appropriate) include —CH═CH—(vinylene), —CH═CH—CH₂—, —CH₂—CH═CH—, —C≡C—, —C≡C—CH₂— and —CH₂—C≡C—.

The C₂₋₃ alkylene group may be substituted by any monodentatesubstituent described above.

Alkoxylene: The term “alkoxylene,” as used herein, pertains to abidentate group of formula —O(CH₂)_(n)O—, where n is 1 or 2.

Includes Other Forms

Unless otherwise specified, included in the above are the well knownionic, salt, solvate, and protected forms of these substituents. Forexample, a reference to carboxylic acid (—COOH) also includes theanionic (carboxylate) form (—COO⁻), a salt or solvate thereof, as wellas conventional protected forms. Similarly, a reference to an aminogroup includes the protonated form (—N⁺HR¹R²), a salt or solvate of theamino group, for example, a hydrochloride salt, as well as conventionalprotected forms of an amino group. Similarly, a reference to a hydroxylgroup also includes the anionic form (—O⁻), a salt or solvate thereof,as well as conventional protected forms of a hydroxyl group.

Isomers, Salts, Solvates and Protected Forms

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric,tautomeric, conformational, or anomeric forms, including but not limitedto, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- andexo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+)and (−) forms; keto-, enol-, and enolate-forms; syn- and anti-forms;synclinal- and anticlinal-forms; α- and β-forms; axial and equatorialforms; boat-, chair-, twist-, envelope-, and halfchair-forms; andcombinations thereof, hereinafter collectively referred to as “isomers”(or “isomeric forms”).

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers”, as used herein, are structural (orconstitutional) isomers (i.e. isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g. C₁₋₇alkyl includesn-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including (wholly or partially)racemic and other mixtures thereof. Methods for the preparation (e.g.asymmetric synthesis) and separation (e.g. fractional crystallisationand chromatographic means) of such isomeric forms are either known inthe art or are readily obtained by adapting the methods taught herein,or known methods, in a known manner.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate, and protected forms of thereof, forexample, as discussed below.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge, et al., J. Pharm. Sci., 66,1-19 (1977).

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g. —COOH may be —COO⁻), then a salt may be formed witha suitable cation. Examples of suitable inorganic cations include, butare not limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthcations such as Ca²⁺ and Mg²⁺, and other cations such as Al⁺³. Examplesof suitable organic cations include, but are not limited to, ammoniumion (i.e. NH₄ ⁺) and substituted ammonium ions (e.g. NH₃R⁺, NH₂R₂ ⁺,NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammonium ions arethose derived from: ethylamine, diethylamine, dicyclohexylamine,triethylamine, butylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline,meglumine, and tromethamine, as well as amino acids, such as lysine andarginine. An example of a common quaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g. —NH₃ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, etharasulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the active compound. The term “solvate” is usedherein in the conventional sense to refer to a complex of solute (e.g.,active compound, salt of active compound) and solvent. If the solvent iswater, the solvate may be conveniently referred to as a hydrate, forexample, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in a chemically protected form. The term “chemicallyprotected form” is used herein in the conventional chemical sense andpertains to a compound in which one or more reactive functional groupsare protected from undesirable chemical reactions under specifiedconditions (e.g. pH, temperature, radiation, solvent, and the like). Inpractice, well known chemical methods are employed to reversibly renderunreactive a functional group, which otherwise would be reactive, underspecified conditions. In a chemically protected form, one or morereactive functional groups are in the form of a protected or protectinggroup (also known as a masked or masking group or a blocked or blockinggroup). By protecting a reactive functional group, reactions involvingother unprotected reactive functional groups can be performed, withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley andSons, 1999).

A wide variety of such “protecting”, “blocking”, or “masking” methodsare widely used and well known in organic synthesis. For example, acompound which has two nonequivalent reactive functional groups, both ofwhich would be reactive under specified conditions, may be derivatizedto render one of the functional groups “protected,” and thereforeunreactive, under the specified conditions; so protected, the compoundmay be used as a reactant which has effectively only one reactivefunctional group. After the desired reaction (involving the otherfunctional group) is complete, the protected group may be “deprotected”to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is converted to a diether (>C(OR)₂), by reaction with, forexample, a primary alcohol. The aldehyde or ketone group is readilyregenerated by hydrolysis using a large excess of water in the presenceof acid.

For example, an amine group may be protected, for example, as an amide(—NRCO—R) or a urethane (—NRCO—OR), for example, as: an acetamide(—NHCO—CH₃); a benzyloxy amide (—NHCO—OCH₂C₆H₅, —NH-Cbz); as a t-butoxyamide (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propoxy amide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxy amide(—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxyamide (—NH-Troc), as an allyloxy amide (—NH-Alloc), as a2(-phenylsulfonyl)ethyloxy amide (—NH-Psec); or, in suitable cases(e.g., cyclic amines), as a nitroxide radical (>N—O).

For example, a carboxylic acid group may be protected as an ester forexample, as: an C₁₋₇ alkyl ester (e.g., a methyl ester; a t-butylester); a C₁₋₇ haloalkyl ester (e.g., a C₁₋₇ trihaloalkyl ester); atriC₁₋₇ alkylsilyl-C₁₋₇ alkyl ester; or a C₅₋₂₀ aryl-C₁₋₇ alkyl ester(e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example,as a methyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; an acetamidomethyl ether(—S—CH₂NHC(═O)CH₃).

The term “treatment”, as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g. in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, amelioration of the condition,and cure of the condition. Treatment as a prophylactic measure (i.e.prophylaxis) is also included.

The term “therapeutically-effective amount”, as used herein, pertains tothat amount of an active compound, or a material, composition or dosageform comprising an active compound, which is effective for producingsome desired therapeutic effect, commensurate with a reasonablebenefit/risk ratio, when administered in accordance with a desiredtreatment regimen. Suitable dose ranges will typically be in the rangeof from 0.01 to 20 mg/kg/day, preferably from 0.1 to 10 mg/kg/day.

Compositions and their Administration

Compositions may be formulated for any suitable route and means ofadministration. Pharmaceutically acceptable carriers or diluents includethose used in formulations suitable for oral, rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural) administration. The formulations may conveniently be presentedin unit dosage form and may be prepared by any of the methods well knownin the art of pharmacy. Such methods include the step of bringing intoassociation the active ingredient with the carrier which constitutes oneor more accessory ingredients. In general the formulations are preparedby uniformly and intimately bringing into association the activeingredient with liquid carriers or finely divided solid carriers orboth, and then, if necessary, shaping the product.

For solid compositions, conventional non-toxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, cellulose,cellulose derivatives, starch, magnesium stearate, sodium saccharin,talcum, glucose, sucrose, magnesium carbonate, and the like may be used.The active compound as defined above may be formulated as suppositoriesusing, for example, polyalkylene glycols, acetylated triglycerides andthe like, as the carrier. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc, an active compound as defined above and optional pharmaceuticaladjuvants in a carrier, such as, for example, water, saline aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, sorbitan monolaurate, triethanolamineoleate, etc. Actual methods of preparing such dosage forms are known, orwill be apparent, to those skilled in this art; for example, seeRemington's Pharmaceutical Sciences, 20th edition, pub. Lippincott,Williams & Wilkins, 2000. The composition or formulation to beadministered will, in any event, contain a quantity of the activecompound(s) in an amount effective to alleviate the symptoms of thesubject being treated.

Dosage forms or compositions containing active ingredient in the rangeof 0.25 to 95% with the balance made up from non-toxic carrier may beprepared.

For oral administration, a pharmaceutically acceptable non-toxiccomposition is formed by the incorporation of any of the normallyemployed excipients, such as, for example, pharmaceutical grades ofmannitol, lactose, cellulose, cellulose derivatives, sodiumcrosscarmellose, starch, magnesium stearate, sodium saccharin, talcum,glucose, sucrose, magnesium carbonate, and the like. Such compositionstake the form of solutions, suspensions, tablets, pills, capsules,powders, sustained release formulations and the like. Such compositionsmay contain 1%-95% active ingredient, more preferably 2-50%, mostpreferably 5-8%.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol or the like. Inaddition, if desired, the pharmaceutical compositions to be administeredmay also contain minor amounts of non-toxic auxiliary substances such aswetting or emulsifying agents, pH buffering agents and the like, such asfor example, sodium acetate, sorbitan monolaurate, triethanolamineoleate, triethanolamine sodium acetate, etc.

The percentage of active compound contained in such parentalcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject. However,percentages of active ingredient of 0.1% to 10% in solution areemployable, and will be higher if the composition is a solid which willbe subsequently diluted to the above percentages. Preferably, thecomposition will comprise 0.2-2% of the active agent in solution.

Ointments are typically prepared from the active compound and aparaffinic or a water-miscible ointment base.

Creams are typically prepared from the active compound and anoil-in-water cream base. If desired, the aqueous phase of the cream basemay include, for example, at least about 30% w/w of a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active compound through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogues.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active compound, such carriers as areknown in the art to be appropriate.

Acronyms

For convenience, many chemical moieties are represented using well knownabbreviations, including but not limited to, methyl (Me), ethyl (Et),n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), sec-butyl (sBu),iso-butyl (iBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex),phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy(MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).

For convenience, many chemical compounds are represented using wellknown abbreviations, including but not limited to, methanol (MeOH),ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), etheror diethyl ether (Et₂O), acetic acid (AcOH), dichloromethane (methylenechloride, DCM), acetonitrile (ACN), trifluoroacetic acid (TFA),dimethylformamide (DMF), tetrahydrofuran (THF), and dimethylsulfoxide(DMSO).

General Synthesis Methods

Compounds where R² is tetrazol-5-yl may be synthesised from compounds offormula 4:

wherein B′ represents the aromatic moiety in B, R′ represents the C_(m)alkylene group in B, and R′ is on the appropriate position on thearomatic moiety, by treatment with sodium azide, trimethyltin azide ortrimethylsilyl azide.

Compounds of formula 4, where D is —C(═O)—N(R^(N))—, may be synthesisedby coupling compounds of Formula 5 and Formula 6a, wherein the groups B′and R′ are as defined above.

Such a coupling step may be carried out using a coupling agent oragents, for example,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, TBTU and DIPEA, or EDC and HOAt.

Compounds of formula 4, where D is —N(R^(N))—C(═O)—, may be synthesisedby coupling compounds of Formula 5′ and Formula 6a′, wherein the groupsB′ and R′ are as defined above.

Such a coupling step may be carried out using a coupling agent oragents, as described above.

Compounds where R² is carboxy, may be synthesised from compounds offormula 7:

wherein B′ and R′ are as defined above, by a hydrolysis reaction, forexample, using sodium hydroxide.

Compounds of formula 7, where D is —C(═O)—N(R^(N))—, can be synthesisedby coupling compounds of formula 5 and 6b, wherein B′ and R′ are asdefined above:

Such a coupling step may be carried out as described above, by using acoupling agent or agents, for example,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, TBTU and DIPEA, or EDC and HOAt.

Compounds of formula 7, where D is —N(R^(N))—C(═O)—, may be synthesisedby coupling compounds of Formula 5′ and Formula 6b′, wherein the groupsB′ and R′ are as defined above.

Such a coupling step may be carried out using a coupling agent oragents, as described above.

Compounds of formula 5, where R⁵ is an aryl group, may be synthesisedfrom compounds of formula 8:

by a Suzuki coupling of a compound of formula 9a (or equivalent ester offormula 9b):

The Suzuki coupling may be achieved using, for example,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) as thepalladium catalyst. Alternatively, the coupling may be achieved usingCsCO₃, with Pd(PPh₃)₄ as the palladium catalyst. In this reaction, thecarboxy group may be protected.

Compounds of Formula 8, where A is:

may be synthesised from compounds of formula 10:

by treating the compound of formula 10 with a brominating agent, such aspyridinium tribromide. This method can be readily adapted for other Agroups.

Compounds of formula 7 where R⁵ is an optionally substituted C₅₋₇ arylgroup may be prepared from compounds of formula 7 where R⁵ is bromine bya Suzuki coupling with compounds of formula 9a or 9b.

Compounds of formula 5, where R⁵ is an alkyl group, and where A is:

may be synthesized from compounds of formula 11:

by reaction with R⁵—Br, in the presence of AlCl₂, in an organic solvent,such as ortho-dichlorobenzene, followed by deprotection of the acidgroup. This method can be readily adapted for other A groups.

Compounds of formula 7, where D is —CH₂—O— or —CH₂—S—, may be preparedby coupling compounds of formula 5″ and 6b″, wherein B′ and R′ are asdefined above:

where X″ is O or S, using NaH in an organic solvent, such as DMF andheptane or THF. Alternatively the coupling may take place before theaddition of the R′CO₂R^(O) group.

A key step in the synthesis of compounds of formula 7, where D is—C(═O)—CH₂—, is the coupling of the remainder of the molecule to R⁵-A.This can be achieved by coupling a compound of formula 12:

or precursor thereof to R⁵-A by a suitable method. For example, when Ais:

the coupling may take place in an organic solvent in the presence ofP₂O₅.

Preferences

The following preferences may be combined with one another, and may bedifferent for each aspect of the present invention.

R⁵ may be a C₅₋₇ aryl group, such as furan-2-yl and phenyl.

R⁵ is preferably a C₆ aryl group, and is more preferably phenyl. R⁵ maybe substituted, and preferred substituents include C₁₋₇ alkoxy groups,more preferably C₁₋₄ alkoxy groups, e.g. —OMe, —OCF₃, —OEt, —OCHF₂, with—OCHF₂ being the most preferred.

When R⁵ is phenyl, preferable substituents include: C₁₋₄ alkyl (e.g.methyl, —CF₃, isopropyl); C₁₋₄ alkoxy (e.g. methoxy, —OCF₃), includingsubstituted C₁₋₄ alkoxy (e.g. benzyloxy); C₅₋₆ aryl (e.g. phenyl); halo(e.g. Cl, F, di-Cl); acyl (e.g. —COMe); amino (e.g. —NH₂, —NMe₂);alkoxylene (e.g. —O—CH₂—O—). In some embodiments, C₁₋₄ alkyl (e.g.methyl, —CF₃, isopropyl); C₁₋₄ alkoxy (e.g. methoxy, —OCF₃); halo (e.g.Cl, F, di-Cl); acyl (e.g. —COMe); and alkoxylene (e.g. —O—CH₂—O—) arepreferred.

The substituents may be any position of the phenyl ring, e.g. 2-, 3- and4-, and when there are two substituents (e.g. di-chloro), these may be,for example, at: 2-,3-; 2-,4-; 3-,5- or 3-,4-.

R⁵ may preferably be furan-2-yl.

R⁵ may preferably be a C₉₋₁₀ aryl group, e.g. napthyl (more preferablynapth-1-yl) and indolyl (more preferably indol-4-yl).

When R⁵ is a C₄₋₂₀ alkyl group, it may be a C₄₋₁₀ alkyl group, andpreferably a branched C₄₋₁₀ alkyl group, e.g. t-butyl, —CH₂—CH(CH₃)₂ ora cyclic alkyl group, such as cyclohexyl or adamantyl. Of these thecyclic groups are more preferred, with adamantyl being the mostpreferred.

When A is a five membered ring:

(i) R³ (if present) is preferably selected from H and optionallysubstituted C₁₋₄ alkyl (in particular, methyl) and is most preferably H;and(ii) R⁴ is preferably selected from H and optionally substituted C₁₋₄alkyl (in particular, methyl) and is most preferably H.

When A is a six-membered ring, it is preferred that either:

(i) R³, R⁴ and R⁶ (if present) are H; or(ii) one of R³, R⁴ and R⁶ (if present) are Cl or F.

One preferred option when A is:

is for R⁴ to be F.

A is preferably selected from:

and is more preferably selected from:

A is most preferably selected from:

The most preferred option for A is:

D is preferably selected from:

and is more preferably:

R^(N) is preferably H or methyl, and is more preferably H.

B is preferably:

and more preferably:

R² is preferably carboxy or tetrazoly-5-yl, with carboxy being mostpreferred.

When R^(P4) is H, R^(P3) is preferably —CH═CH—R².

In some embodiments, m and n can only be 0 or 1, and m+n can only be 1or 2. In these embodiments, preferably n+m=1, and more preferably n is 0and m is 1.

In other embodiments, it is preferred that n is 0, and one of R^(P3) andR^(P4) (preferably R^(P3)) is —O—CH₂—R², wherein R² is preferablycarboxy or tetrazol-5-yl, more preferably carboxy.

In some embodiments, the compound is of formula (Ia):

or of formula (Ib):

Particularly preferred compounds of the present invention include:

-   {4-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid (2);-   4-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid (4);-   4-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid (10);-   (3-[(5-(4-Methoxy-phenyl)-furan-2-carbonyl)-amino]-phenyl)-acetic    acid (12);-   (3-[(5-(4-Dimethylamino-phenyl)-furan-2-carbonyl)-amino]-phenyl)-acetic    acid (14); and-   3-{4-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-propionic acid    (16).

Further particularly preferred compounds of the invention include:

-   (3-{[5-(2-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (17);-   (3-{[5-(3-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (18);-   (3-{[5-(3-Acetyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (19);-   (3-{[5-(4-Acetyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (20);-   (3-{[5-(3-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (21);-   (3-{[5-(4-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (22);-   (3-{[5-(2-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (23);-   (3-{[5-(3-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (24);-   (3-{[5-(2,4-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (25);-   (3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (26);-   (3-{[5-(3,4-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (27);-   (3-{[5-(2-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (28);-   (3-{[5-(4-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (29);-   (3-{[5-(2-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (30);-   (3-{[5-Naphthalen-1-yl-furan-2-carbonyl)-amino]-phenyl}-acetic acid    (31);-   (3-{[5-(3-Trifluoromethoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (32);-   (3-{[5-(4-Trifluoromethoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (33);-   (3-{[5-(3-Isopropyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (34);-   (3-{[5-(4-Isopropyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (35);-   {3-[(5-Benzo[1,3]dioxol-5-yl-furan-2-carbonyl)-amino]-phenyl}-acetic    acid (36);-   (3-{[5-(2,3-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (37);-   {3-[([2,2′]Bifuranyl-5-carbonyl)-amino]-phenyl}-acetic acid (38);-   (3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (39);-   (3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (40);-   3-{[5-(1H-Indol-5-yl)-furan-2-carbonyl]-amino}-phenyl)-acetic acid    (41);-   (3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (42);-   {3-[(5-Phenyl-thiophene-2-carbonyl)-amino]-phenyl}-acetic acid (43);-   {3-[(4-Chloro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (44);-   {3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-acetic acid (45);-   {3-[(6-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (46);-   {3-[(3-Methyl-biphenyl-4-carbonyl)-amino]-phenyl}-acetic acid (47);-   {3-[(3-Chloro-biphenyl-4-carbonyl)-amino]-phenyl}-acetic acid (48)-   {3-[(Biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (49);-   {3-[(4-Methyl-5-phenyl-thiophene-2-carbonyl)-amino]-phenyl}-acetic    acid (50);-   {3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (51);-   ({3-[(5-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (52);-   {3-[(2-Phenyl-1H-imidazole-5-carbonyl)-amino]-phenyl}-acetic acid    (53);-   {3-[(2-Phenyl-thiazole-4-carbonyl)-amino]-phenyl}-acetic acid (54);-   3-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid (57);-   5-[(5-Phenyl-furan-2-carbonyl)-amino]-1H-indole-2-carboxylic acid    (59);-   3-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-acrylic acid (61);-   3-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-propionic acid    (62);-   6-[(5-Phenyl-furan-2-carbonyl)-amino]-naphthalene-2-carboxylic acid    (63);-   (3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-acetic    acid (66);-   (3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-acetic    acid (68);-   3-(3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic    acid (69);-   3-(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic    acid (70);-   3-(3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic    acid (71);-   5-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-1H-indole-2-carboxylic    acid (72);-   5-Phenyl-furan-2-carboxylic acid (3-carbamoylmethyl-phenyl)-amide    (73);-   Phenyl-furan-2-carboxylic acid [3-(2-hydroxy-ethyl)-phenyl]-amide    (74); and-   5-Phenyl-furan-2-carboxylic acid    [3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (75).

Further particularly preferred compounds of the invention include:5-Phenyl-furan-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide(177);

-   5-(3-Chloro-phenyl)-furan-2-carboxylic acid    [3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (81);-   5-(3,5-Dichloro-phenyl)-furan-2-carboxylic acid    [3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (82);-   5-(4-Fluoro-phenyl)-furan-2-carboxylic acid    [3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (85);-   5-(3-Fluoro-phenyl)-furan-2-carboxylic acid    [3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (86);-   5-(4-Chloro-phenyl)-furan-2-carboxylic acid    [3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (87);-   5-Phenyl-furan-2-carboxylic acid    {3-[2-(1H-tetrazol-5-yl)-vinyl]-phenyl}-amide (89);-   5-(3-Chloro-phenyl)-furan-2-carboxylic acid    {3-[2-(1H-tetrazol-5-yl)-vinyl]-phenyl}-amide (90);-   6-Phenyl-pyridine-2-carboxylic acid    [3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (92);-   6-(4-Fluoro-phenyl)-pyridine-2-carboxylic acid    [3-(1H-tetrazol-5ylmethyl)-phenyl]-amide (93);-   6-(3-Fluoro-phenyl)-pyridine-2-carboxylic acid    [3-(1H-tetrazol-5ylmethyl)-phenyl]-amide (94);-   6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid    [3-(1H-tetrazol-5ylmethyl)-phenyl]-amide (95);-   5-[(5-Phenyl-furan-2-carbonyl)-amino]-benzofuran-2-carboxylic acid    (96);-   5-[(5-Phenyl-furan-2-carbonyl)-amino]-benzo[b]thiophene-2-carboxylic    acid (97);-   2-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-benzylidene}-butyric acid    (98);-   3-(3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic    acid (100);-   3-{3-[(5-Benzo[1,3]dioxol-5-yl-furan-2-carbonyl)-amino]-phenyl}-acrylic    acid (101);-   3-(3-{[5-(3,5-Bis-trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}phenyl)-acrylic    acid (102);-   3-{3-[(5-Biphenyl-3-yl-furan-2-carbonyl)-amino]-phenyl}-acrylic acid    (103);-   3-(3-{[5-(3-Benzyloxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic    acid (104);-   3-(3-{[5-(2-Fluoro-biphenyl-4-yl)-furan-2-carbonyl]-amino}-phenyl)-acrylic    acid (105);-   3-{3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylic acid    (107);-   3-{3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylic    acid (108);-   3-(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylic    acid (110);-   3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid    (111);-   3-{3-[(4,4′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylic    acid (112);-   (3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acetic    acid (113);-   3-{3-[(2-Phenyl-thiazole-4-carbonyl)-amino]-phenyl}-acrylic acid    (115);-   3-(3-{[2-(3-Fluoro-phenyl)-thiazole-4-carbonyl]-amino}-phenyl)-acrylic    acid (116);-   [3-(Biphenyl-3-ylcarbamoyl)-phenyl]-acetic acid (117);-   1-Methyl-5-[(5-phenyl-furan-2-carbonyl)-amino]-1H-indole-2-carboxylic    acid (118);-   3-{3-[2—Oxo-2-(5-phenyl-furan-2-yl)-ethyl]-phenyl}-acrylic acid    (120);-   3-[3-(2-Phenyl-thiazol-4-ylmethoxy)-phenyl]-acrylic acid (121);-   3-[3-(2-Phenyl-thiazol-4-ylmethylsulfanyl)-phenyl]-acrylic acid    (122);-   3-{3-[(5-Adamantan-1-yl-furan-2-carbonyl)-amino]-phenyl}-acrylic    acid (123);-   3-(3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionic    acid (125);-   3-(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionic    acid (126);-   (3-{[5-(3,5-Difluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (127);-   (3-{[5-(3-fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic    acid (128);-   (3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acetic    acid (129);-   (3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acetic    acid (130);-   3-(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylic    acid (132);-   (3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-acetic    acid (133);-   3-(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-propionic    acid (134);-   5-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-1H-indole-2-carboxylic    acid (135);-   3-(3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylic    acid (137);-   (3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-acetic    acid (138);-   {3-[(3′-Chloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic    acid (140);-   3-{3-[(3′-Chloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylic    acid (142);-   {3-[(3′,5′-Dichloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic    acid (143);-   3-{3-[(3′,5′-Dichloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylic    acid (144);-   3-(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic    acid (146);-   3-(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionic    acid (147);-   3-(3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionic    acid (148);-   (3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acetic    acid (150);-   3-(3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylic    acid (151);-   (3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acetic    acid (153);-   (3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-acetic    acid (154);-   3-(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylic    acid (155);-   (3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-acetic    acid (156);-   (3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-acetic    acid (157);-   (3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-acetic    acid (158);-   3-(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]amino}-phenyl)-propionic    acid (159);-   {3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenoxy}-acetic acid (160);-   3-(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-propionic    acid (162);-   3-(3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionic    acid (163);-   3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-propionic acid    (164);-   3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid (165);-   3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-propionic acid    (167);-   (3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-acetic    acid (168);-   {3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid    (169);-   (3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-acetic    acid (170);-   {3-[(4,4′-Difluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid    (171);-   5-Phenyl-furan-2-carboxylic acid    [3-(1H-tetrazol-5-ylmethoxy)-phenyl]-amide (173);-   6-Phenyl-pyridine-2-carboxylic acid    [3-(1H-tetrazol-5-ylmethoxy)-phenyl]-amide (174);-   6-Phenyl-pyridine-2-carboxylic acid    {3-[2-(1H-tetrazol-5-yl)-vinyl]phenyl}-amide (175); and-   4-Fluoro-biphenyl-3-carboxylic acid    {3-[2-(1H-tetrazol-5-yl)-vinyl]phenyl}-amide (176).

The selectivity of the compound for modulating EP₂ receptors over one ormore of the other EP receptors (i.e. EP₂, EP₂, EP₄) can be quantified bydividing the Ki for EP₂ (see below) by the Ki for the other EP receptors(see below). The resulting ratio is preferably 10 or more, morepreferably 100 or more.

SYNTHESIS EXAMPLES General Experimental Details

Petroleum ether refers to that fraction with a boiling point of 40-60°C.

Organic solutions were dried over magnesium sulphate unless otherwisespecified.

General Experimental Details for Examples 1 to 5

All reactions were carried out under an inert atmosphere of nitrogen.

PS-TsCl refers to Polystyrene scavenger resin (loading 1.97mmol/g)-Argonaut Technologies (P/N 800277)

LC/MS Systems

The Liquid Chromatography Mass Spectroscopy (LC/MS) systems used are asfollows.

LC/MS System A:

-   -   Mass Spectrometer—Platform LC with electrospray source operating        in positive and negative ion mode. HP1100 system running at 2.0        mL/min, 200 μL/min split to the ESI source with inline HP1100        DAD detection and SEDEX ELS detection.    -   Mobile Phase    -   A) Water 0.1% Formic Acid    -   B) acetonitrile 0.1% Formic Acid    -   Gradient

Time Flow (min) (mL/min) % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 595 5.00 2.0 5 95 5.50 2.0 95 5

-   -   Column Luna 3u C18(2) 30×4.6 mm

LC/MS System B:

-   -   Mass Spectrometer—Platform II with electrospray source operating        in negative ion mode. HP1100 system running at 2.0 mL/min, 200        μL/min split to the ESI source with inline HP1100 DAD detection        and SEDEX ELS detection.    -   Mobile Phase    -   A) Water 0.1 Diethylamine    -   B) acetonitrile    -   Gradient

Time Flow (min) (mL/min) % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.00 2.0 595 4.50 2.0 5 95 5.00 2.0 95 5 20.00 2.0 95 5

-   -   Column—XTerra MS C18 3.5 μm 4.6×30 mm

LCMS System C:

-   -   Mass Spectrometer—Finnigan TSQ700 with electrospray source        operating in negative ion mode.        -   HP1050 system running at 2.0 mL/min, 200 μL/min split to the            ESI source with inline HP1050 Single wavelength UV detector            at 254 nm.    -   Mobile Phase    -   A) Water 0.1% Diethylamine    -   B) acetonitrile    -   Gradient

Time Flow (min) (mL/min) % A % B 0.00 2.0 95 5 1.00 2.0 95 5 15.00 2.0 595 17.00 2.0 5 95 18.00 2.0 95 5 20.00 2.0 95 5

-   -   Column —XTerra MS C18 3.5 μm 4.6×30 mm

LC/MS System D:

-   -   Mass Spectrometer—Finnigan TSQ700 with electrospray source        operating in positive or negative ion mode. HP1050 system        running at 2.0 mL/min, 200 μL/min split to the ESI source with        inline HP1050 Single Wavelength UV detector at 254 nm.    -   Mobile Phase    -   A) Water 0.1% formic Acid    -   B) acetonitrile 0.1% formic Acid    -   Gradient

Time Flow (min) (mL/min) % A % B 0.00 2.0 95 5 1.00 2.0 95 5 15.00 2.0 595 17.00 2.0 5 95 18.00 2.0 95 5 20.00 2.0 95 5

-   -   Column Higgins Clipius C18 5 μm 100×3.0 mm

Example 1 Synthesis of{4-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid (2)

(a) {4-[(5-phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid ethylester (1)

Diispropylethylamine (300 μl) was added to a stirred solution of5-phenyl-furan-2-carboxylic acid (73.5 mg, 0.39 mmol) andethyl-4-aminophenyl acetate (70 mg, 0.39 mmoles) inN,N-dimethylformamide (10 ml).O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (200 mg, 0.52 mmoles) was added and the solution wasstirred at room temperature for 72 hours. The solvent was evaporated,the residue was dissolved in dichloromethane and washed with water, 10%aqueous sodium carbonate, 1 M aqueous hydrochloric acid and finallydried (MgSO₄). After evaporation of the solvent, the residue wastriturated with cyclohexane and dried to afford (1) (82 mg) as a gum.LC/MS System A; R_(t)=3.80 mins, m/z (ES⁺)=350 (M+H for C₂₁H₁₉NO₄).

(b) {4-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid (2)

A solution of sodium hydroxide (100 mg) in water (5 ml) was added to astirred solution of{4-[(5-phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester(1) (75 mg, 0.214 mmoles) in ethanol (10 ml) and the mixture was stirredat room temperature for 1 hour. The solvent was evaporated and theresidue was diluted with water (10 ml) and acidified to pH=2 with 1 Maqueous hydrochloric acid. The precipitate was collected, washed withwater and the residue was triturated with cyclohexane to afford (2)(61.5 mg) as a white solid. LC/MS System D; R_(t)=3.01 mins, m/z(ES−)=320 (M−H for C₁₉H₁₅NO₄.

Example 2 Synthesis of4-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid (4)

(a) 4-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid ethylester (3)

In an analogous manner to Example 1(a), compound (3) was synthesisedfrom 5-phenyl-furan-2-carboxylic acid (73.5 mg, 0.39 mmol) and4-aminomethyl-benzoic acid ethyl ester (70 mg, 0.39 mmoles). 80 mg ofthe product was obtained as a gum. LC/MS System A; R_(t)=3.69 mins, m/z(ES⁺)=350 (M+H for C₂₁H₁₉NO₄).

(b) 4-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid (4)

In an analogous manner to Example 1(b), compound (4) was synthesisedfrom compound (3) (72 mg, 0.206 mmoles). 51 mg of the product wasobtained as a white solid. LC/MS System C; R_(t)=2.74 mins, m/z(ES⁻)=320 (M−H for C₁₉H₁₅NO₄).

Example 3 Synthesis of3-{4-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-propionic acid (16)

(a) 3-{4-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-propionic acidethyl ester (15)

In an analgous manner to Example 2(a), compound (15) was synthesisedfrom 5-phenyl-furan-2-carboxylic acid and 3-(4-amino-phenyl)-propionicacid ethyl ester.

(b) 3-{4-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-propionic acid (16)

In an analogous manner to Example 2(b), compound (16) was synthesisedfrom compound (15).

Example 4 Synthesis of4-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid (10) (a)Ethyl-3-aminophenyl acetate (6)

A stirred solution of 3-aminophenyl acetic acid (1 g, 6.6 mmoles) (5)and conc. sulphuric acid (2 ml) in ethanol (20 ml) was refluxed for 3hours. The solvent was evaporated and the residue dissolved in ethylacetate, washed with water, sodium carbonate, brine, water, and finallydried (MgSO₄. After concentrating in vacuo (6) (918 mg) was obtained asdark red oil.

(b) 5-phenyl-furan-2-carboxylic acid methyl ester (7)

A mixture of methyl 5-bromofuroate (1 g, 5 mmoles), phenylboronic acid(1 g, 8.2 mmoles), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.17mmoles), sodium carbonate (1.5 g, 17.4 mmoles) in toluene (100 ml) wasrefluxed for 16 hours. After cooling, the solvent was evaporated and theyellow residue was portioned between water (50 ml) and ethyl acetate (50ml). The aqueous layer was extracted with ethyl acetate (3×30 ml) andthe combined organic layers washed with water (1×30 ml) and dried(MgSO₄. The residue was purified by flash chromatography (20% ethylacetate/70% cyclohexane and 10% diethyl ether/90% cyclohexane) to afford(7) (384 mg). This ester was used directly in the next step.

(c) 5-phenyl-furan-2-carboxylic acid (8)

A solution of sodium hydroxide (200 mg) in water (5 ml) was added to astirred solution of 5-phenyl-furan-2-carboxylic acid methyl ester (7)(384 mg, 1.90 mmoles) in methanol (20 ml) and the mixture was stirred atroom temperature for 4 hours. The solvent was evaporated and the residuewas diluted with water (10 ml) and acidified to pH=2 with 1 M aqueoushydrochloric acid. The precipitate was collected, washed with water andthe residue was triturated with cyclohexane to afford (8) (350 mg) as awhite solid. LC/MS System A; R_(t)=3.89 mins.

(d) {3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid ethylester (9)

In an analgous manner to Example 1(a), compound (9) was synthesised from5-phenyl-furan-2-carboxylic acid (8) (73.5 mg, 0.390 mmoles) andethyl-3-aminophenyl acetate (6) (70 mg, 0.390 mmoles). 80 mg of theproduct was obtained as a gum. LC/MS System D; R_(t)=3.83 mins, m/z(ES⁺)=350 (M+H for C₂₁H₁₉NO₄).

(e) {3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-acetic acid (10)

In an analogous manner to Example 1(b), compound (10) was synthesisedfrom compound (9) (70 mg, 0.200 mmoles). 44 mg of the product wasobtained as a white solid. LC/MS System D; R_(t)=2.90 mins, m/z(ES⁻)=320 (M−H for C₁₉H₁₅NO₄).

Example 5 Synthesis of(3-[(5-(4-Methoxy-phenyl)-furan-2-carbonyl)-amino]-phenyl)-acetic acid(12) and(3-[(5-(4-Dimethylamino-phenyl)-furan-2-carbonyl)-amino]-phenyl)-aceticacid (14)

(a) (3-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl)-acetic acid ethylester (11)

To a solution of 5-bromo-2-furoic acid (1.14 g) and 3-aminophenylaceticacid ethyl ester (1.06 g) in anhydrous DMF (15 ml) was addeddiisopropylamine (2.1 ml) and thenO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (2.259). The solution was stirred at roomtemperature for 16 hours then partitioned between ethyl acetate andwater. The organic layer was separated, washed twice with 1Mhydrochloric acid, water, aqueous sodium carbonate solution, brine,dried over sodium sulphate and evaporated in vacuo. Compound 11 (1.8 g)was obtained following silica gel column chromatography of the residuein 2:1 ethyl acetate:petroleum ether.

¹H NMR (CDCl₃, δ): 1.2 (3H, t); 3.65 (2H, s); 4.2 (2H, q); 6.5 (1H, d);7.1 (1H, d); 7.25 (1H, d); 7.35 (1H, t); 7.6 (2H, c); 8.0 (1H, broad s).

(b) (3-[(5-(4-Methoxy-phenyl)-furan-2-carbonyl)-amino]-phenyl)-aceticacid (12)

(i) To a previously degassed mixture of(3-[(5-bromo-furan-2-carbonyl)-amino]-phenyl)-acetic acid ethyl ester(11) (0.4 g), 4-methoxyphenylboronic acid (0.19 g), potassium carbonate(0.39 g) and tetra-n-butylammonium bromide (0.37 g) in water (2 ml) wasadded palladium II acetate (circa 10 mg). The mixture was heated to 70°C. for an hour, cooled and partitioned between ethyl acetate and water.The organic layer was separated, washed with brine, dried over sodiumsulphate and evaporated in vacuo.(3-[(5-(4-Methoxy-phenyl)-furan-2-carbonyl)-amino]-phenyl)-acetic acidethyl ester (0.4 g) was obtained following silica gel columnchromatography of the residue in 2:1 ethyl acetate:petroleum ether.

(ii) The product of the previous step was hydrolysed in IMS (80 ml) bythe addition of a solution of sodium hydroxide (0.65 g) in water (21ml). The resulting solution was stirred at room temperature for 2 hoursthen evaporated in vacuo below 40° C. The residue was dissolved indichloromethane, washed with 2M hydrochloric acid and the aqueous layerback-extracted with dichloromethane. The organic layers were combined,dried over sodium sulphate, filtered and evaporated in vacuo. Compound12 (0.28 g; m.p. 179-180° C.) was obtained following trituration of theresidue in a mixture of dichloromethane and pentane.

¹H NMR (d₆-DMSO, δ): 3.6 (2H, s); 3.8 (3H, s); 7.0 (4H, c); 7.25 (1H,t); 7.4 (1H, d); 7.65 (2H, c); 7.9 (2H, d); 10.1 (1H, s); 12.4 (1H,broad s); m/z=374.0 (M+Na)⁺; microanalysis for C₂₀H₁₇NO₅. 0.25H₂O: C,expected 67.50; found 67.46; H, expected 4.96; found 4.85; N, expected3.94; found 3.89.

(c)(3-[(5-(4-Dimethylamino-phenyl)-furan-2-carbonyl)-amino]-phenyl)-aceticacid ethyl ester (13)

To a previously degassed mixture of(3-[(5-bromo-furan-2-carbonyl)-amino]-phenyl)-acetic acid ethyl ester(11) (0.4 g), 4-(dimethylamino)phenylboronic acid (0.239), potassiumcarbonate (0.39 g) and tetra-n-butylammonium bromide (0.37 g) in water(2 ml) was added palladium II acetate (circa 10 mg). The mixture washeated to 70° C. for an hour, cooled and partitioned between ethylacetate and water. The organic layer was separated, washed with brine,dried over sodium sulphate and evaporated in vacuo. Compound 13(0.33 g)was obtained following silica gel column chromatography of the residuein 2:3 ethyl acetate:petroleum ether.

¹H NMR (d₆-DMSO, δ): 1.2 (3H, t); 2.95 (6H, s); 3.6 (2H, s); 4.1 (2H,q); 6.75 (2H, d); 6.85 (1H, d); 7.0 (1H, m); 7.3 (1H, t); 7.35 (1H, d);7.65 (2H, c); 7.8 (2H, d); 10.05 (1H, s).

(d)(3-[(5-(4-Dimethylamino-phenyl)-furan-2-carbonyl)-amino]-phenyl)-aceticacid (14)

To a solution of(3-[(5-(4-dimethylamino-phenyl)-furan-2-carbonyl)-amino]-phenyl)-aceticacid ethyl ester (13) (0.33 g) in IMS (80 ml) was added a solution ofsodium hydroxide (0.65 g) in water (21 ml). The resulting solution wasstirred at room temperature for 1 hour then concentrated in vacuo below40° C. to circa 15 ml volume. Water (50 ml) then acetic acid (1.5 ml)were added and the resulting precipitate filtered, washed with water andtriturated with dichloromethane/pentane to yield the title compound(0.26 g; m.p. 187-190° C.).

¹H NMR (d₆-DMSO, δ): 2.95 (6H, s); 3.6 (2H, s); 6.75 (2H, d); 6.85 (1H,d); 7.0 (1H, m); 7.3 (1H, t); 7.35 (1H, d); 7.65 (2H, c); 7.8 (2H, d);10.05 (1H, s); m/z=387.1 (M+Na)⁺; microanalysis for C₂₁H₂₀N₂O₄.0.2H₂O:C, expected 68.54; found 68.77; H, expected 5.59; found 5.83; N,expected 7.61; found 7.26.

General Experimental Details for Examples 6 to 8

Commercially available reagents and solvents (HPLC grade) were usedwithout further purification.

Microwave irradiation was carried out using a CEM Discover focusedmicrowave reactor.

¹H NMR spectra were recorded on a Bruker 400 MHz AV spectrometer indeuterated solvents. Chemical shifts (δ) are in parts per million andcoupling constants are expressed in Hz. Thin-layer chromatography (TLC)analysis was performed with Kieselgel 60 F₂₅₄ (Merck) plates andvisualized using UV light.

Analytical HPLC-MS was performed on Agilent HP1100, Waters 600 or Waters1525 LC systems using reverse phase Hypersil BDS C18 columns (5 μm,2.1×50 mm), gradient 0-95% B (A=water/0.1% TFA, B=acetonitrile/0.1% TFA)over 2.10 min, flow=1.0 ml/min. UV spectra were recorded at 215 nm usinga Gilson G1315A Diode Array Detector, G1214A single wavelength UVdetector, Waters 2487 dual wavelength UV detector, Waters 2488 dualwavelength UV detector, or Waters 2996 diode array UV detector. Massspectra were obtained over the range m/z 150 to 850 at a sampling rateof 2 scans per second or 1 scan per 1.2 seconds using Micromass LCT withZ-spray interface or Micromass LCT with Z-spray or MUX interface. Datawere integrated and reported using OpenLynx and OpenLynx Browsersoftware.

Purification of compounds by preparative HPLC was performed on Gilsonsystems using reverse phase ThermoHypersil-Keystone Hyperprep HS C18columns (12 μm, 100×21.2 mm), gradient 20-100% B (A=water/0.1% TFA,B=acetonitrile/0.1% TFA) over 9.5 min, flow=30 ml/min, injection solvent2:1 DMSO:acetonitrile (1.6 ml), UV detection at 215 nm.

Common Methods

In the following examples, the following common methods A to J areemployed.

Thionyl chloride (1 eq) was added dropwise to MeOH (15 vol) at 0° C.followed 10 min later by careful addition of a solution of carboxylicacid (1 eq) in MeOH (5 vol) at 0° C. The reaction mixture was allowed towarm to room temperature then stirred for 3 h. The reaction mixture wasevaporated in vacuo to give the ester.

A solution of carboxylic acid (1 eq) was heated under reflux for 18 hwith H₂SO₄ (0.5 vol) in MeOH or EtOH (25 vol). The solvent wasevaporated in vacuo and the residue partitioned between DCM and aqueoussodium bicarbonate. The DCM layer was washed with brine, dried (Na₂SO₄),filtered and the solvent removed in vacuo to give the ester.

To a stirred solution of carboxylic acid (1 eq) and amino acid ester (1eq) in DMF (20 vol) was added DIPEA (1 eq) followed by TBTU (1 eq). Thereaction was stirred overnight, or until complete by LC/MS, at roomtemperature. To the reaction mixture was added EtOAc (30 vol) and theorganic layer was washed with 2M HCl (2×50 vol), brine (2×50 vol),saturated aqueous NaHCO₃ (2×50 vol) and brine (2×50 vol). The organiclayer was dried (MgSO₄), filtered and the solvent removed in vacuo togive the product.

The carboxylic acid (1 eq), EDC (1.2 eq), and HOAt (1.2 eq) were addedto a vial as solids. The amino ester was dissolved in DMF (10 vol) andadded to the vial. The reaction was stirred at room temperatureovernight or until complete by LC/MS. Water (20 vol) was added and themixture was extracted with and EtOAc (3×10 vol). The organic layer wasthen washed with water (10 vol), dried (MgSO₄), filtered andconcentrated in vacuo. Column chromatography using a stepped gradient ofEtOAc in heptane gave the product.

To a suspension of the aryl bromide (1 eq), Cs₂CO₃ (1.2 eq) and boronicacid (1.1 eq) in toluene (15 vol) and MeOH (4 vol) was added Pd(PPh₃)₄(0.1 eq). The resulting mixture was heated in a CEM discover microwavefor 30 mins at 120° C. (150 W, 250 psi). Analysis was carried out byLC-MS and, if required, the reaction was heated again to drive thereaction to completion. Once complete, the reaction mixture was filteredthrough celite and the solvents removed in vacuo. The crude residue wasre-dissolved in EtOAc and washed with water (3×5 vol). The combinedorganic layers were dried (Na₂SO₄), filtered and the solvents removed invacuo. The compounds were then purified by column chromatography.

If the ester group present was ethyl ester then EtOH was used instead ofMeOH

E1) In some cases, LC-MS analysis showed that partial hydrolysisoccurred during reaction. In this case, after the solvents were removedin vacuo, the residue was re-dissolved in EtOAc (1.5 vol) and theorganic layer was washed with 1M HCl (2×1 vol), dried (Na₂SO₄), filteredand the solvent removed in vacuo. The residue was triturated with TBME(1.5 vol).

To a suspension of the aryl bromide (1.2 eq), Cs₂CO₂ (4.0 eq) andboronic acid (1 eq) in toluene (5 vol) and EtOH (5 vol) under N₂ wasadded Pd(PPh₃)₄ (0.05 eq) and the resulting mixture was heated to 85° C.for 3 h. The solvents were removed in vacuo and the solids re-suspendedin EtOAc (10 vol). Water (10 vol) was then added and all the solidsdissolved. The layers were separated and the aqueous layer was washedwith EtOAc (3×5 vol) and acidified to pH 4 with 2M HCl upon which aprecipitate formed. This was then extracted with EtOAc (2×10 vol). Thecombined organic layers were dried (Na₂SO₄) and removed in vacuo to givethe product.

To a solution of the ester in THF (1.5 ml) was added NaOH (18 eq) inwater (0.5 ml) and the resulting solution was stirred for 1 h at roomtemperature. The THF was removed under a stream of N₂ then EtOAc (2 ml)and water (1 ml) were added. The aqueous layer was extracted with EtOAc(2×2 ml) and acidified with 2M HCl until a white precipitate formed.This was then extracted with EtOAc (3×2 ml). The solvent was removed invacuo to give the product.

To a solution of ethyl ester in EtOH (2 ml) was added 1M NaOH (2 ml) andthe resulting solution was stirred for 30 min at room temperature. TheEtOH was then removed in vacuo and the residue re-dissolved in TBME (20ml) and water (20 ml). The aqueous layer was extracted with TBME (2×20ml) then acidified with 2M HCl until a white precipitate formed. Thiswas then extracted with EtOAc (3×20 ml). The combined organic layerswere washed with brine, dried (Na₂SO₄), filtered and the solvent removedin vacuo to give the product.

The nitro ester was dissolved in EtOH (6 vol) and NH₄COOH (4 eq) wasadded as a solid. 5% Palladium on carbon (10% by weight) was then addedunder N₂ and the resulting mixture heated to reflux under N₂ for 30 min.The reaction mixture was filtered through celite and the celite waswashed with EtOH (20 vol). The solvent was removed in vacuo to give theproduct.

The nitro derivative was dissolved in EtOH (5 vol) and SnCl₂.2H₂O (50eq) was added as a solid. The resulting solution was then stirred at 60°C. for 2 h. After cooling to room temperature, a pre-mixed solution ofsaturated Rochelle's salt (10 vol) and saturated NaHCO₃ (10 vol) wasadded to the reaction mixture and the aqueous layer was extracted withEtOAc (3×20 vol). The combined organic layers were dried (MgSO₄) and thesolvent removed in vacuo to afford the product.

To a solution of nitrile (1 eq) in toluene (4 vol) was added Me₃SnN₃(1.1 eq). After heating to reflux for 18 h, analysis was carried out byLC-MS. If required, additional Me₃SnN₃ (1.1 eq) and toluene (3 vol) wereadded and the reaction heated again to drive the reaction to completion.2M NaOH (3 vol) and hexane (3 vol) were then added to the reactionmixture and stirred for 10 min. Water (1.5 vol) was added and theorganic layer separated. EtOAc (3 vol) was added to the aqueous layerand the solution stirred for 2 min before the organic layer wasseparated. The combined organic layers were discarded. The aqueous layerwas then acidified to pH 5 with 2M HCl then EtOAc (3.5 vol) was addedand the solution stirred for 10 min after which time the organic layerwas separated. Further EtOAc (3.5 vol) was added to the aqueous layerand the solution stirred for 1 hour. The EtOAc layer was separated andthese combined organic layers were evaporated in vacuo.

To a suspension of the nitrile (1 eq) in DME (2 vol) were added TMSN₃ (4eq) and Bu₂SnO (0.2 eq). The resulting mixture was heated in a CEMDiscover microwave for 40 min at 150° C. (150 W, 250 psi). Analysis wascarried out by LC-MS and, if required, the mixture was heated again todrive the reaction to completion. Once complete, EtOAc (3.5 vol) and H₂O(3.5 vol) were added. The layers were separated, and the organic layerwas washed with a saturated NaHCO₃ solution (3×3.5 vol). The aqueouslayer was acidified with 2M HCl until a white precipitate appeared, thenextracted with EtOAc (3×3.5 vol). The solvent was removed under a streamof N₂.

To a solution of ester in EtOH or MeOH (5 vol), water (5 vol) and THF(10 vol) was added LiOH (20 eq.) and the resulting solution was stirredfor 4 h at room temperature. ROH and THF were removed under a stream ofN₂ and the remaining aqueous layer acidified using 1M HCl until a whiteprecipitate appeared. The aqueous layer was then extracted using EtOAc(2×20 vol). This organic layer was dried (Na₂SO₄), filtered and thesolvent removed in vacuo.

Example 6 a)(3-{[5-(2-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acid(17) (i) (3-Amino-phenyl)-acetic acid methyl ester (15)

3-Aminophenylacetic acid (5 g, 33.1 mmol) was esterified with MeOH usingMethod B to give the title compound

Yield: 4.22 g, 77%; LC/MS t_(r) 0.70 min; MS(ES+) m/z 166 (M+H).

(ii) {3-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-acetic acid methylester (16)

Methyl ester (15) (1 g, 6.06 mmol) was coupled to5-bromo-furan-2-carboxylic acid (1.16 g, 6.07 mmol) using Method C togive the title compound

Yield: 1.83 g, 89%; LC/MS t_(r) 1.34 min; MS(ES+) m/z 338, 340 (M+H).

(iii) (3-{[5-(2-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to2-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. Thecrude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 18 mg, 17%; LC/MS t_(r) 1.54 min; MS(ES+) m/z 366 (M+H).

(iv) (3-{[5-(2-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (17)

The ester (18.4 mg, 0.050 mmol) was hydrolysed with NaOH (36 mg, 0.9mmol) using Method G to give the title compound.

Yield: 5.6 mg, 32%; LC/MS t_(r) 1.45 min; MS(ES+) m/z 352 (M+H); HPLCPurity: 99%; ¹H NMR (250 MHz; MeOD): δ 3.65 (s, 2H), 4.05 (s, 3H),7.1-7.2 (m, 4H), 7.3-7.45 (m, 3H), 7.65-7.75 (m, 2H), 8.25 (s, 1H).

b) (3-{[5-(3-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (18) (i)(3-{[5-(3-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. Thecrude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 13 mg, 12%; LC/MS t_(r) 1.48 min; MS(ES+) m/z 366 (M+H).

(ii) (3-{[5-(3-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (18)

The ester (13 mg, 0.035 mmol) was hydrolysed with NaOH (25 mg, 0.63 mmolusing Method G to give the title compound.

Yield: 8.2 mg, 66%; LC/MS t_(r) 1.41 min; MS(ES+) m/z 352 (M+H); HPLCPurity: 99%; ¹H NMR (250 MHz; MeOD): δ 3.70 (s, 2H), 3.95 (s, 3H),6.95-7.05 (m, 2H), 7.10-7.15 (m, 1H), 7.3-7.45 (m, 3H), 7.50-7.6 (m,2H), 7.65-7.75 (m, 2H).

c) (3-{[5-(3-Acetyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acid(19) (i)(3-{[5-(3-Acetyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3-acetyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crudecompound was purified by column chromatography, eluting in 17% EtOAc inheptane to give the title compound.

Yield: 11 mg, 10%; LC/MS t_(r) 1.46 min; MS(ES+) m/z 378 (M+H).

(ii) (3-{[5-(3-Acetyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (19)

The ester (11 mg, 0.028 mmol) was hydrolysed with NaOH (20 mg, 0.5 mmol)using Method G to give the title compound.

Yield: 10 mg, 98%; LC/MS t_(r) 1.34 min; MS(ES+) m/z 364 (M+H).

HPLC Purity: 92%; ¹H NMR (250 MHz; MeOD): δ 2.5 (s, 3H), 3.45 (s, 2H),6.9 (s, 2H), 7.10-7.20 (m, 2H), 7.35-7.5 (m, 3H), 7.8 (d, 1H), 7.95 (d,1H), 8.35 (s, 1H).

d) (3-{[5-(4-Acetyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acid(20) (1)(3-{[5-(4-Acetyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to4-acetyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crudecompound was purified by column chromatography, eluting in 17% EtOAc inheptane to give the title compound.

Yield: 26 mg, 23%; LC/MS t_(r) 1.45 min; MS(ES+) m/z 378 (M+H).

(ii) (3-{[5-(4-Acetyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (20)

The ester (26 mg, 0.068 mmol) was hydrolysed with NaOH (49 mg, 1.22mmol) using Method G to give the title compound.

Yield: 22 mg, 87%; LC/MS t_(r) 1.35 min; MS(ES+) m/z 364 (M+H).

HPLC Purity: 87%; ¹H NMR (400 MHz; MeOD): δ 2.6 (s, 3H), 3.65 (s, 2H),7.10-7.20 (m, 2H), 7.30-7.40 (m, 2H), 7.70 (s, 2H), 8.05-8.10 (m, 4H).

(e) (3-{[5-(3-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (21) (i)(3-{[5-(3-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crudecompound was purified by column chromatography, eluting in 17% EtOAc inheptane to give the title compound.

Yield: 20 mg, 19%; LC/MS t_(r) 1.59 min; MS(ES+) m/z 350 (M+H).

(ii) (3-{[5-(3-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (21)

The ester (20 mg, 0.057 mmol) was hydrolysed with NaOH (41 mg, 1.03mmol) using Method G to give the title compound.

Yield: 15 mg, 78%; LC/MS t_(r) 1.41 min; MS(ES+) m/z 336 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD): δ 2.35 (s, 3H), 3.5 (s, 2H); 6.9(s, 1H), 7.0-7.05 (m, 1H), 7.1-7.15 (m, 1H), 7.20-7.30 (m, 3H), 7.5 (s,1H), 7.60-7.65 (m, 2H), 7.7 (s, 1H).

(f) (3-{[5-(4-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (22) (i)(3-{[5-(4-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to4-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crudecompound was purified by column chromatography, eluting in 17% EtOAc inheptane to give the title compound.

Yield: 45 mg, 44%; LC/MS t_(r) 1.60 min; MS(ES+) m/z 350 (M+H).

(ii) (3-{[5-(4-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (22)

The ester (45 mg, 0.13 mmol) was hydrolysed with NaOH (94 mg, 2.34 mmol)using Method G.

Yield: 36 mg, 84%; LC/MS t_(r) 1.41 min; MS(ES+) m/z 336 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD): δ 2.2 (s, 3H), 3.45 (s, 2H), 6.7(d, 1H), 6.9 (d, 1H), 7.05-7.15 (m, 4H), 7.45-7.50 (m, 2H), 7.65 (d,2H).

(g)(3-{[5-(2-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (23) (i)(3-{[5-(2-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to2-trifluoromethyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E.The crude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 55 mg, 46%; LC/MS t_(r) 1.62 min; MS(ES+) m/z 404 (M+H).

(ii)(3-{[5-(2-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (23)

The ester (55 mg, 0.14 mmol) was hydrolysed with NaOH (100 mg, 2.52mmol) using Method G to give the title compound.

Yield: 47 mg, 89%; LC/MS t_(r) 1.42 min; MS(ES+) m/z 390 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD): δ 3.8 (s, 2H), 7.05-7.10 (m, 1H),7.25-7.30 (m, 1H), 7.45-7.60 (m, 2H), 7.75-7.85 (m, 3H), 7.90-7.95 (m,1H), 8.00-8.05 (m, 1H), 8.15-8.2 (m, 1H).

(h)(3-{[5-(3-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (24) (i)(3-{[5-(3-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3-trifluoromethyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E.The crude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 30 mg, 25%; LC/MS t_(r) 1.65 min; MS(ES+) m/z 404 (M+H).

(ii)(3-{[5-(3-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (24)

The ester (30 mg, 0.074 mmol) was hydrolysed with NaOH (53 mg, 1.33mmol) using Method G to give the title compound.

Yield: 25 mg, 87%; LC/MS t_(r) 1.46 min; MS(ES+) m/z 390 (M+H); HPLCPurity: 92%; ¹H NMR (400 MHz; MeOD): δ 3.45 (s, 2H), 7.00-7.05 (m, 2H),7.15-7.20 (m, 1H), 7.3 (d, 1H), 7.45 (s, 1H), 7.55-7.60 (m, 3H),8.05-8.10 (m, 1H), 8.25 (s, 1H).

(j) (3-{[5-(2,4-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (25) (i)(3-{[5-(2,4-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to2,4-dichloro-phenylboronic acid (61 mg, 0.33 mmol) using Method E. Thecrude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 37 mg, 31%; LC/MS t_(r) 1.76 min; MS(ES+) m/z 404, 406 (M+H).

(ii)(3-{[5-(2,4-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (25)

The ester (37 mg, 0.091 mmol) was hydrolysed with NaOH (66 mg, 1.64mmol) using Method G to give the title compound.

Yield: 9.1 mg, 25%; LC/MS t_(r) 1.96 min; MS(ES+) m/z 390, 392 (M+H);HPLC Purity: 100%; ¹H NMR (400 MHz; MeOD): δ 3.5 (s, 2H), 7.0 (d, 1H),7.2-7.25 (m, 2H), 7.3 (d, 1H), 7.4 (d, 1H), 7.5 (s, 1H), 7.6 (2H), 8.1(1H).

(k) (3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (26) (i)(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3,5-dichloro-phenylboronic acid (61 mg, 0.33 mmol) using Method E. Thecrude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 11 mg, 9%; LC/MS t_(r) 1.76 min; MS(ES+) m/z 404, 406 (M+H).

(ii)(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (26)

The ester (11 mg, 0.027 mmol) was hydrolysed with NaOH (20 mg, 0.49mmol) using Method G to give the title compound.

Yield: 9.6 mg, 91%; LC/MS t_(r) 1.97 min; MS(ES+) m/z 390, 392 (M+H);HPLC Purity: 100%; ¹H NMR (400 MHz; MeOD): δ 3.55 (s, 2H), 7.00-7.05 (m,2H), 7.20-7.30 (m, 2H), 7.35 (s, 1H), 7.55-7.60 (m, 2H), 7.9 (s, 2H).

(l) (3-{[5-(3,4-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (27) (i)(3-{[5-(3,4-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3,4-dichloro-phenylboronic acid (61 mg, 0.33 mmol) using Method E. Thecrude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 33 mg, 27%; LC/MS t_(r) 1.70 min; MS(ES+) m/z 404, 406 (M+H).

(ii)(3-{[5-(3,4-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (27)

The ester (33 mg, 0.081 mmol) was hydrolysed with NaOH (58 mg, 1.46mmol) using Method G to give the title compound.

Yield: 24 mg, 76%; LC/MS t_(r) 1.92 min; MS(ES+) m/z 390, 392 (M+H);HPLC Purity: 87%; ¹H NMR (400 MHz; MeOD): δ 3.5 (s, 2H), 6.95-7.05 (m,2H), 7.20-7.25 (m, 2H), 7.45-7.50 (m, 1H), 7.55-7.60 (m, 2H), 7.7 (d,1H), 8.1 (s, 1H).

(m) (3-{[5-(2-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (28) (i)(3-{[5-(2-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to2-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crudecompound was purified by column chromatography, eluting in 17% EtOAc inheptane to give the title compound.

Yield: 60 mg, 58%; LC/MS t_(r): 1.55 min; MS(ES+) m/z 350 (M+H).

(ii) (3-{[5-(2-Methyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (28)

The ester (60 mg, 0.17 mmol) was hydrolysed with NaOH (122 mg, 3.06mmol) using Method G to give the title compound.

Yield: 41 mg, 71%; LC/MS t_(r) 1.84 min; MS(ES+) m/z 336 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD): δ 2.4 (s, 3H), 3.5 (s, 2H), 6.7(d, 1H), 7.0 (d, 1H), 7.15-7.20 (m, 4H), 7.28-7.30 (m, 1H), 7.50-7.60(m, 2H), 7.75-7.85 (m, 1H).

(n) (3-{[5-(4-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (29) (i)(3-{[5-(4-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to4-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. Thecrude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 50 mg, 46%; LC/MS t_(r) 1.49 min; MS(ES+) m/z 366 (M+H).

(ii) (3-{[5-(4-Methoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (29)

The ester (50 mg, 0.14 mmol) was hydrolysed with NaOH (100 mg, 2.52mmol) using Method G to give the title compound.

Yield: 45 mg, 93%; LC/MS t_(r) 1.79 min; MS(ES+) m/z 352 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD): δ 3.5 (s, 2H), 3.7 (s, 3H), 6.7(s, 1H), 6.9 (d, 2H), 7.0 (d, 1H), 7.20-7.25 (m, 2H), 7.55-7.60 (m, 2H),7.70-7.80 (m, 2H).

(o) (3-{[5-(2-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (30) (i)(3-{[5-(2-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to2-chloro-phenylboronic acid (51 mg, 0.33 mmol) using Method E. The crudecompound was purified by column chromatography, eluting in 17% EtOAc inheptane to give the title compound.

Yield: 38 mg, 34%; LC/MS t_(r) 1.58 min; MS(ES+) m/z 370, 372 (M+H).

(ii) (3-{[5-(2-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (30)

The ester (38 mg, 0.10 mmol) was hydrolysed with NaOH (72 mg, 1.8 mmol)using Method G to give the title compound.

Yield: 35 mg, 95%; LC/MS t_(r) 1.86 min; MS(ES+) m/z 356, 358 (M+H);HPLC Purity: 97%; ¹H NMR (400 MHz; MeOD): δ 3.5 (s, 2H), 6.95-7.00 (m,1H), 7.20-7.30 (m, 4H), 7.30-7.38 (m, 1H), 7.40-7.45 (m, 1H), 7.55-7.60(m, 2H), 8.10 (d, 1H).

(p) (3-{[5-Naphthalen-1-yl-furan-2-carbonyl)-amino]-phenyl}-acetic acid(31) (i) (3-{[5-Naphthalen-1-yl-furan-2-carbonyl)-amino]-phenyl}-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to1-naphthaleneboronic acid (56 mg, 0.33 mmol) using Method E. The crudecompound was purified by column chromatography, eluting in 17% EtOAc inheptane to give the title compound.

Yield: 12 mg, 10%; LC-MS t_(r)1.62 min; MS(ES+) m/z 386 (M+H).

(ii) {3-[(5-Naphthalen-1-yl-furan-2-carbonyl)-amino]-phenyl}-acetic acid(31)

The ester (12 mg, 0.031 mmol) was hydrolysed with NaOH (22 mg, 0.56mmol) using Method G to give the title compound.

Yield: 8.7 mg, 76%; LC/MS t_(r) 1.87 min; MS(ES+) m/z 372 (M+H); HPLCPurity: 89%; ¹H NMR (250 MHz; MeOD) δ 4.52 (s, 2H), 6.88 (d, 1H), 7.00(d, 1H), 7.18-7.27 (t, 1H), 7.39 (d, 1H), 7.43-7.58 (m, 5H), 7.80-7.89(m, 3H), 8.29 (d, 1H).

(q)(3-{[5-(3-Trifluoromethoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (32) (i)(3-{[5-(3-Trifluoromethoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3-(trifluoromethoxy)-phenylboronic acid (67 mg, 0.33 mmol) using MethodE. The crude compound was purified by column chromatography, eluting in17% EtOAc in heptane to give the title compound.

Yield: 23 mg, 18%; LC-MS t_(r)1.63 min; MS(ES+) m/z 420 (M+H).

(ii)(3-{[5-(3-Trifluoromethoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (32)

The ester (23 mg, 0.055 mmol) was hydrolysed with NaOH (40 mg, 0.99mmol) using Method G to give the title compound.

Yield: 22 mg, 100%; LC/MS t_(r) 1.90 min; MS(ES+) m/z 406 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz; MeOD) δ 3.66 (s, 2H), 7.10-7.16 (m, 2H),7.28-7.40 (m, 3H), 7.59 (t, 1H), 7.67-7.73 (m, 2H), 7.90-7.98 (m, 2H).

(r)(3-{[5-(4-Trifluoromethoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (33) (i)(3-{[5-(4-Trifluoromethoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

The methyl ester (16) (100 mg, 0.30 mmol) was coupled to4-(trifluoromethoxy)-phenylboronic acid (67 mg, 0.33 mmol) using MethodE. The crude compound was purified by column chromatography, eluting in17% EtOAc in heptane to give the title compound.

Yield: 65 mg, 52%; LC-MS t_(r)1.62 min; MS(ES+) m/z 420 (M+H).

(ii)(3-{[5-(4-Trifluoromethoxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (33)

The ester (65 mg, 0.15 mmol) was hydrolysed with NaOH (0.11 mg, 2.7mmol) using Method G to give the title compound.

Yield: 47 mg, 75%; LC/MS t_(r) 1.91 min; MS(ES+) m/z 406 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz; MeOD) δ 3.65 (s, 2H), 7.06 (d, 1H), 7.12(d, 1H), 7.31-7.42 (m, 4H), 7.66-7.72 (m, 2H), 8.08 (d, 2H).

(s) (3-{[5-(3-Isopropyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (34) (i)(3-{[5-(3-Isopropyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3-isopropyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. Thecrude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 30 mg, 27%; LC-MS t_(r)1.70 min; MS(ES+) m/z 378 (M+H).

(ii) (3-{[5-(3-Isopropyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (34)

The ester (30 mg, 0.080 mmol) was hydrolysed with NaOH (58 mg, 1.44mmol) using Method G to give the title compound.

Yield: 29 mg, 100%; LC/MS t_(r) 1.54 min; MS(ES+) m/z 364 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD) δ 1.20 (d, 6H), 2.90 (sept, 1H),3.53 (s, 2H), 6.87 (d, 1H), 7.00 (d, 1H), 7.17 (d, 1H), 7.20-7.29 (m,3H), 7.52-7.59 (m, 2H), 7.63 (d, 1H), 7.72 (s, 1H).

(t) (3-{[5-(4-Isopropyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (35) (i)(3-{[5-(4-Isopropyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to4-isopropyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. Thecrude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 33 mg, 30%; LC-MS t_(r)1.70 min; MS(ES+) m/z 378 (M+H).

(ii) (3-{[4-Isopropyl-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (35)

The ester (33 mg, 0.087 mmol) was hydrolysed with NaOH (63 mg, 1.57mmol) using Method G to give the title compound.

Yield: 32 mg, 100%; LC/MS t_(r) 1.56 min; MS(ES+) m/z 364 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD) δ 1.19 (d, 6H), 2.86 (sept, 1H),3.52 (s, 2H), 6.82 (d, 1H), 7.00 (d, 1H), 7.18-7.27 (m, 4H), 7.53-7.60(m, 2H), 7.75 (d, 2H).

(u) {3-[(5-Benzo[1,3]dioxol-5-yl-furan-2-carbonyl)-amino]-phenyl}-aceticacid (36) (i){3-[(5-Benzo[1,3]dioxol-5-yl-furan-2-carbonyl)-amino]-phenyl}-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3,4-(methylenedioxy)-phenylboronic acid (54 mg, 0.33 mmol) using MethodE. The crude compound was purified by column chromatography, eluting in17% EtOAc in heptane to give the title compound.

Yield: 25 mg, 22%; LC-MS t_(r)1.46 min; MS(ES+) m/z 380 (M+H).

(ii){3-[(5-Benzo[1,3]dioxol-5-yl-furan-2-carbonyl)-amino]-phenyl}-aceticacid (36)

The ester (25 mg, 0.066 mmol) was hydrolysed with NaOH (48 mg, 1.19mmol) using Method G to give the title compound.

Yield: 16 mg, 66%; LC/MS t_(r): 1.32 min; MS(ES+) m/z 366 (M+H); HPLCPurity: 97%; ¹H NMR (250 MHz; MeOD) δ 3.67 (s, 2H), 6.03 (s, 2H), 6.85(d, 1H), 6.93 (d, 1H), 7.12 (d, 1H), 7.31-7.39 (m, 2H), 7.45-7.51 (m,2H), 7.65-7.72 (m, 2H).

(v) (3-{[5-(2,3-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (37) (i)(3-{[5-(2,3-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to2,3-dichloro-phenylboronic acid (62 mg, 0.33 mmol) using Method E. Thecrude compound was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 15 mg, 13%; LC-MS t_(r)1.72 min; MS(ES+) m/z 404, 406 (M+H).

(ii)(3-{[5-(2,3-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (37)

The ester (15 mg, 0.037 mmol) was hydrolysed with NaOH (27 mg, 0.67mmol) using Method G to give the title compound.

Yield: 12 mg, 80%; LC/MS t_(r) 1.91 min; MS(ES+) m/z 390, 392 (M+H);HPLC Purity: 96%; ¹H NMR (400 MHz; MeOD) δ 3.54 (s, 2H), 7.01 (d, 1H),7.20-7.28 (m, 2H), 7.29-7.37 (m, 2H), 7.49 (d, 1H), 7.53-7.59 (m, 2H),8.03 (d, 1H).

(w) {3-[([2,2′]Bifuranyl-5-carbonyl)-amino]-phenyl}-acetic acid (38) (i){3-[([2,2′]Bifuranyl-5-carbonyl)-amino]-phenyl}-acetic acid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to furan-2-boronicacid (37 mg, 0.33 mmol) using Method E. The crude compound was purifiedby column chromatography, eluting in 17% EtOAc in heptane to give thetitle compound.

Yield: 13 mg, 13%; LC-MS t_(r) 1.41 min; MS(ES+) m/z 326 (M+H).

(ii) {3-[([2,2′]Bifuranyl-5-carbonyl)-amino]-phenyl}-acetic acid (38)

The ester (13 mg, 0.040 mmol) was hydrolysed with NaOH (29 mg, 0.72mmol) using Method G to give the title compound.

Yield: 11 mg, 88%; LC/MS t_(r) 1.70 min; MS(ES+) m/z 312 (M+H); HPLCPurity: 94%; NMR (400 MHz; MeOD) 6.3.56 (s, 2H), 6.50 (d, 1H), 6.67 (d,1H), 6.88 (d, 1H), 7.00 (d, 1H), 7.19-7.23 (m, 2H), 7.49-7.58 (m, 3H).

(x) (3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (39) (i)(3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to3-chlorophenylboronic acid (51 mg, 0.33 mmol) using Method E. The crudecompound was purified by column chromatography, eluting in 17% EtOAc inheptane to give the title compound.

Yield: 29 mg, 26%; LC/MS t_(r) 1.58 min; MS(ES+) m/z 370, 372 (M+H).

(ii) (3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (39)

The ester (29 mg, 0.076 mmol) was hydrolysed with NaOH (55 mg, 1.37mmol) using Method G to give the title compound.

Yield: 27 mg, 100%; LC/MS t_(r) 1.86 min; MS(ES+) m/z 356, 358 (M+H);HPLC Purity: 100%; ¹H NMR (250 MHz; MeOD): δ 3.66 (s, 2H), 7.06-7.14 (m,2H), 7.32-7.49 (m, 4H), 7.69-7.70 (m, 2H), 7.86 (d, 1H), 8.07 (s, 1H).

(y) (3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (40) (i)(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acidmethyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to4-chloro-phenylboronic acid (51 mg, 0.33 mmol) using Method E. The crudecompound was purified by column chromatography, eluting in 17% EtOAc inheptane to give the title compound.

Yield: 34 mg, 31%; LC/MS t_(r) 1.59 min; MS(ES+) m/z 370, 372 (M+H).

(ii) (3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (40)

The ester (34 mg, 0.092 mmol) was hydrolysed with NaOH (66 mg, 1.66mmol) using Method G to give the title compound.

Yield: 23 mg, 70%; LC/MS t_(r) 1.86 min; MS(ES+) m/z 356, 358 (M+H);HPLC Purity: 94%; ¹H NMR (250 MHz; MeOD): δ 3.34 (s, 2H), 7.15 (d, 1H),7.12 (d, 1H), 7.36 (m, 2H), 7.48 (m, 2H), 7.69 (m, 2H), 7.94 (m, 2H).

(z) 3-{[5-(1H-Indol-5-yl)-furan-2-carbonyl]-amino}-phenyl)-acetic acid(41) (i) 3-{[5-(1H-Indol-5-yl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid methyl ester

Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 1H-indole-5-boronicacid (52 mg, 0.33 mmol) using Method E. The crude compound was purifiedby column chromatography, eluting in 20% EtOAc in heptane to give thetitle compound.

Yield: 22 mg, 20%; LC/MS t_(r) 1.14 min; MS(ES+) m/z 375 (M+H).

(ii) 3-{[5-(1H-Indol-5-yl)-furan-2-carbonyl]-amino}-phenyl)-acetic acid(41)

The ester (22 mg, 0.059 mmol) was hydrolysed with NaOH (42 mg, 1.06mmol) using Method G to give the title compound.

Yield: 8.8 mg, 41%; LC/MS t_(r) 1.29 min; MS(ES+) m/z 361 (M+H); HPLCPurity: 94%; ¹H NMR (400 MHz; DMSO): b 3.60 (s, 2H), 6.65 (s, 1H), 7.03(d, 2H), 7.32 (t, 1H), 7.43 (d, 2H), 7.50 (d, 1H), 7.70 (m, 3H), 8.22(s, 1H), 10.15 (s, 1H), 11.30 (s, 1H).

(aa) (3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (42) (i) Alternate synthesis of (3-Amino-phenyl)-acetic acid ethylester (6)

3-Aminophenylacetic acid (2 g, 13 mmol) was esterified with EtOH usingMethod B to give the title compound.

Yield: 2.1 g, 89%; LC/MS t_(r) 0.78 min; MS(ES+) m/z 180 (M+H).

(ii) 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid (76)

4-Fluoro-phenylboronic acid (611 mg, 4.4 mmol) was coupled to5-bromo-2-furoic acid (1 g, 5.2 mmol) using Method F to give the titlecompound.

Yield: 350 mg, 38%; LC/MS t_(r) 1.24 min; MS(ES+) m/z 207 (M+H).

(iii) (3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid ethyl ester

(3-Amino-phenyl)-acetic acid ethyl ester (44 mg, 0.24 mmol) was coupledto 5-(4-fluoro-phenyl)-furan-2-carboxylic acid (76) (50 mg, 0.24 mmol)using Method C. The crude compound was purified by columnchromatography, eluting in 20% EtOAc in heptane to give the titlecompound.

Yield: 90 mg, 100%; LC/MS t_(r) 1.59 min; MS(ES+) m/z 368 (M+H).

(iv) (3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (42)

To a solution of ester (90 mg, 0.25 mmol) in MeOH (0.09 ml) was added 1MNaOH (1 ml) and the reaction mixture was stirred for 3 h at roomtemperature. The MeOH was evaporated under a stream of N₂. The aqueouslayer was washed with DCM (0.5 ml) and acidified to pH 4 with 2M HCluntil a white precipitate formed. This was then extracted with EtOAc(0.5 ml). The organic layer was dried (Na₂SO₄), filtered, and thesolvent removed in vacuo to give the title compound.

Yield: 25 mg, 30%; LC/MS t_(r) 1.42 min; MS(ES+) m/z 339 (M+H); HPLCPurity: 95%; ¹H NMR (360 MHz; MeOD): δ 3.53 (s, 2H), 6.84 (d, 1H), 7.00(d, 1H), 7.10 (m, 2H), 7.23 (m, 2H), 7.56 (m, 2H), 7.87 (m, 2H).

(bb) Alternate synthesis of(3-{[5-(phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acid (10) (i)(3-{[5-(phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acid methylester

Methyl ester (16) (500 mg, 1.48 mmol) was coupled to phenylboronic acid(150 mg, 1.23 mmol) using Method E. The crude compound was purified bycolumn chromatography, eluting with a stepped gradient of 20-25% EtOAcin heptane to give the title compound.

Yield: 120 mg, 29%; LC/MS t_(r) 1.51 min; MS(ES+) m/z 336 (M+H).

(ii) (3-{[5-(phenyl)-furan-2-carbonyl]-amino}-phenyl)-acetic acid (10)

To a solution of ester (112 mg, 0.33 mmol) in THF (1.1 ml) was addedNaOH (112 mg, 2.8 mmol) in water (1.1 ml) and the resulting solution wasstirred for 6 h at room temperature. The THF was removed under a streamof N₂ and the aqueous layer was acidified to pH 4 using 1M HCl. Theaqueous layer was extracted with DCM (2×2 ml) and the combined organiclayers evaporated in vacuo to give the title compound.

Yield: 97 mg, 91%; LC/MS t_(r) 1.36 min; MS(ES+) m/z 322 (M+H); HPLCPurity: 99%; ¹H NMR (360 MHz; DMSO): δ 3.63 (s, 2H), 7.08 (d, 1H), 7.25(d, 2H), 7.37 (t, 1H), 7.47 (m, 2H), 7.56 (t, 2H), 7.71 (s, 1H), 7.77(d, 2H), 8.04 (d, 2H), 10.24 (s, 1H), 12.45 (s, 1H).

Example 7 (a) {3-[(5-Phenyl-thiophene-2-carbonyl)-amino]-phenyl}-aceticacid (43) (i) {3-[(5-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-aceticacid ethyl ester

5-Bromothiophene-2-carboxylic acid (232 mg, 1.1 mmol) was coupled withethyl ester (6) (201 mg, 1.1 mmol) following Method C to give the titlecompound.

Yield: 220 mg, 54%; LC/MS t_(r) 1.54 min; MS(ES+) m/z 368, 370 (M+H).

(ii) {3-[(5-Phenyl-thiophene-2-carbonyl)-amino]-phenyl}-acetic acidethyl ester

{3-[(5-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-acetic acid ethylester (220 mg, 0.60 mmol) was coupled to phenylboronic acid using MethodE except that the reaction mixture was heated at 80° C. for 25 min undermicrowave conditions. The crude product was purified by columnchromatography using 33% EtOAc in heptane to give the title compound.

Yield: 128 mg, 58%; LC/MS t_(r) 1.61 min; MS(ES+) m/z 366 (M+H).

(iii) {3-[(5-Phenyl-thiophene-2-carbonyl)-amino]-phenyl}-acetic acid(43)

The ethyl ester (75 mg, 0.21 mmol) was hydrolysed using Method H to givethe title compound.

Yield: 44 mg, 63%; LC/MS t_(r) 1.50 min; MS(ES+) m/z 338 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, MeOD) δ 3.62 (s, 2H), 7.08-7.10 (m, 1H),7.29-7.46 (m, 5H), 7.60-7.62 (m, 2H), 7.70-7.72 (m, 2H), 7.88 (d, 1H).

(b) {3-[(4-Chloro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (44)(i) [3-(5-Bromo-2-chloro-benzoylamino)-phenyl]-acetic acid ethyl ester

5-Bromo-2-chlorobenzoic acid (132 mg, 0.56 mmol) was coupled with ethylester (6) (100 mg, 0.56 mmol) following Method C to give the titlecompound.

Yield: 198 mg, 89%; LC/MS t_(r) 1.55 min; MS(ES+) m/z 396, 398 (M+H).

(ii) {3-[(4-Chloro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid ethylester

[3-(5-Bromo-2-chloro-benzoylamino)-phenyl]-acetic acid ethyl ester (198mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, exceptthat the reaction mixture was heated at 80° C. for 25 min. The crudeproduct was purified by column chromatography using 20% EtOAc in heptaneto give the title compound.

Yield: 86 mg, 44%; LC/MS t_(r) 1.66 min; MS(ES+) m/z 394, 396 (M+H).

(iii) {3-[(4-Chloro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (44)

The ethyl ester (86 mg, 0.22 mmol) was hydrolysed using Method H to givethe title compound.

Yield: 62 mg, 78%; LC/MS t_(r) 1.48 min; MS(ES+) m/z 366, 368 (M+H);HPLC Purity: 92%; ¹H NMR (400 MHz, MeOD) δ 3.65 (s, 2H), 7.13 (d, 1H),7.33-7.50 (m, 4H), 7.58-7.82 (m, 7H).

(c) {3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-acetic acid (45)(i) {3-[(6-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-acetic acid ethylester (77)

6-Bromo-2-pyridinecarboxylic acid (113 mg, 0.56 mmol) was coupled withethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the titlecompound.

Yield: 198 mg, 97%; LC/MS t_(r) 1.52 min; MS(ES+) m/z 363, 365 (M+H).

(ii) {3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-acetic acid ethylester

{3-[(6-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester(77) (198 mg, 0.54 mmol) was coupled to phenylboronic acid using MethodE, except that the reaction mixture was heated at 80° C. for 25 min. Thecrude product was purified by column chromatography using 20% EtOAc inheptane to give the title compound.

Yield: 129 mg, 66%; LC/MS t_(r) 1.70 min; MS(ES+) m/z 361 (M+H).

(iii) {3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-acetic acid (45)

The ethyl ester (129 mg, 0.36 mmol) was hydrolysed using Method H togive the title compound.

Yield: 100 mg, 84%; LC/MS t_(r) 1.49 min; MS(ES+) m/z 333 (M+H); HPLCPurity: 96%; ¹H NMR (400 MHz, MeOD) δ 3.69 (s, 2H), 7.15 (d, 1H),7.37-7.42 (m, 1H), 7.50-7.60 (m, 3H), 7.78-7.80 (m, 2H), 8.08-8.23 (m,5H).

(d) {3-[(6-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (46)(i) [3-(3-Bromo-4-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester

3-Bromo-4-fluorobenzoic acid (123 mg, 0.56 mmol) was coupled with ethylester (6) (100 mg, 0.56 mmol) following Method C to give the titlecompound.

Yield: 190 mg, 89%; LC/MS t_(r) 1.55 min; MS(ES+) m/z 380, 382 (M+H).

(ii) {3-[(6-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid ethylester

[3-(3-Bromo-4-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester (190mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, exceptthat the reaction mixture was heated at 80° C. for 25 min. The crudeproduct was purified by column chromatography using 20% EtOAc in heptaneto give the title compound.

Yield: 106 mg, 56%; LC/MS t_(r) 1.67 min; MS(ES+) m/z 378 (M+H).

(iii) {3-[(6-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (46)

The ethyl ester (106 mg, 0.28 mmol) was hydrolysed using Method H togive the title compound.

Yield: 83 mg, 84%; LC/MS t_(r) 1.51 min; MS(ES+) m/z 350 (M+H); HPLCPurity: 92%; ¹H NMR (400 MHz, MeOD) δ 3.65 (s, 2H), 7.12 (d, 1H),7.33-7.53 (m, 5H), 7.63-7.67 (m, 4H), 7.97-8.01 (m, 1H), 8.10-8.12 (m,1H).

(e) {3-[(3-Methyl-biphenyl-4-carbonyl)-amino]-phenyl}-acetic acid (47)(i) [3-(4-Bromo-2-methyl-benzoylamino)-phenyl]-acetic acid ethyl ester

4-Bromo-2-methylbenzoic acid (120 mg, 0.56 mmol) was coupled with ethylester (6) (100 mg, 0.56 mmol) following Method C to give the titlecompound

Yield: 188 mg, 89%; LC/MS t_(r) 1.53 min; MS(ES+) m/z 376, 378 (M+H).

(ii) {3-[(3-Methyl-biphenyl-4-carbonyl)-amino]-phenyl}-acetic acid ethylester

[3-(4-Bromo-2-methyl-benzoylamino)-phenyl]-acetic acid ethyl ester (188mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, exceptthat the reaction mixture was heated at 80° C. The crude residue waspurified by column chromatography using 20% EtOAc in heptane to give thetitle compound.

Yield: 87 mg, 47%; LC/MS t_(r) 1.73 min; MS(ES+) m/z 374 (M+H).

(iii) {3-[(3-Methyl-biphenyl-4-carbonyl)-amino]-phenyl}-acetic acid (47)

The ethyl ester (87 mg, 0.23 mmol) was hydrolysed using Method H to givethe title compound.

Yield: 52 mg, 65%; LC/MS t_(r) 1.84 min; MS(ES+) m/z 346 (M+H); HPLCPurity: 96%; ¹H NMR (400 MHz, MeOD) δ 2.56 (s, 3H), 3.64 (s, 2H), 7.13(d, 1H), 7.33-7.41 (m, 2H), 7.46-7.51 (m, 2H), 7.58-7.69 (m, 7H).

(f) {3-[(3-Chloro-biphenyl-4-carbonyl)-amino]-phenyl}-acetic acid (48)(i) [3-(4-Bromo-2-chloro-benzoylamino)-phenyl]-acetic acid ethyl ester

4-Bromo-2-chlorobenzoic acid (132 mg, 0.56 mmol) was coupled with ethylester (6) (100 mg, 0.56 mmol) following Method C to give the titlecompound.

Yield: 198 mg, 89%; LC/MS t_(r) 1.57 min; MS(ES+) m/z 396, 398 (M+H).

(ii) {3-[(3-Chloro-biphenyl-4-carbonyl)-amino]-phenyl}-acetic acid ethylester

[3-(4-Bromo-2-chloro-benzoylamino)-phenyl]-acetic acid ethyl ester (198mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, exceptthat the reaction mixture was heated at 80° C. The crude residue waspurified by column chromatography using 20% EtOAc in heptane to give thetitle compound.

Yield: 100 mg, 51%; LC/MS t_(r) 1.67 min; MS(ES+) m/z 394, 396 (M+H).

(iii) {3-[(3-Chloro-biphenyl-4-carbonyl)-amino]-phenyl}-acetic acid (48)

The ethyl ester (100 mg, 0.25 mmol) was hydrolysed using Method H togive the title compound.

Yield: 90 mg, 97%; LC/MS t_(r) 1.84 min; MS(ES+) m/z 366, 368 (M+H);HPLC Purity: 96%; ¹H NMR (250 MHz, MeOD) δ 3.64 (s, 2H), 7.13 (d, 1H),7.32-7.55 (m, 4H), 7.64-7.79 (m, 7H).

(g) {3-[(Biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (49) (i)[3-(3-Bromo-benzoylamino)-phenyl]-acetic acid ethyl ester

3-Bromo-benzoic acid (112 mg, 0.56 mmol) was coupled with ethyl ester(6) (100 mg, 0.56 mmol) following Method C to give the title compound.

Yield: 203 mg, 100%; LC/MS t_(r) 1.56 min; MS(ES+) m/z 362, 364 (M+H).

(ii) {3-[(Biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid ethyl ester

[3-(3-Bromo-benzoylamino)-phenyl]-acetic acid ethyl ester (203 mg, 0.56mmol) was coupled to phenylboronic acid using Method E, except that thereaction mixture was heated at 80° C. The crude residue was purified bycolumn chromatography using 20% EtOAc in heptane to give the titlecompound.

Yield: 142 mg, 70%; LC/MS t_(r) 1.65 min; MS(ES+) m/z 360 (M+H).

(iii) {3-[(Biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (49)

The ethyl ester (140 mg, 0.39 mmol) was hydrolysed using Method H togive the title compound.

Yield: 85 mg, 66%; LC/MS t_(r) 1.49 min; MS(ES+) m/z 332 (M+H); HPLCPurity: 97%; ¹H NMR (250 MHz, MeOD) δ 3.65 (s, 2H), 7.13 (d, 1H),7.32-7.44 (m, 2H), 7.47-7.54 (m, 2H), 7.59-7.75 (m, 5H), 7.85-7.96 (m,2H), 8.21-8.22 (m, 1H).

(h) {3-[(4-Methyl-5-phenyl-thiophene-2-carbonyl)-amino]-phenyl}-aceticacid (50) (i) 4-Methyl-5-phenyl-thiophene-2-carboxylic acid (methyl andethyl) ester

5-Bromo-4-methyl-thiophene-2-carboxylic acid methyl ester (120 mg, 0.51mmol) was coupled to phenylboronic acid using Method E, except that thereaction mixture was heated at 80° C. in EtOH/toluene. The crude residuewas purified by column chromatography using 10% EtOAc in heptane to givethe title compound as a mixture of the methyl and ethyl esters.

Yield: 108 mg (combined); LC/MS t_(r): 1.69 min (Me), 1.78 min (Et);MS(ES+) m/z 233 [(M+H) Me]; 247 [(M+H) Et]; HPLC Purity: 98% (59% Me,39% Et).

(ii) 4-Methyl-5-phenyl-thiophene-2-carboxylic acid

To a solution of 4-methyl-5-phenyl-thiophene-2-carboxylic acid (methyland ethyl) ester (106 mg, ˜0.45 mmol) in MeOH (5 ml) was added 1M NaOH(5 ml) and the resulting solution was stirred for 30 min at roomtemperature. The MeOH was then removed in vacuo. DCM (20 ml) and water(20 ml) were added and the aqueous layer extracted with DCM (2×20 ml).The aqueous layer was acidified with 2M HCl until a white precipitateformed. This was then extracted with EtOAc (3×20 ml). The combinedorganic layers were washed with brine (20 ml), dried (Na₂SO₄), filteredand the solvent removed in vacuo to give the title compound.

Yield: 25 mg, 25%; LC/MS t_(r) 1.42 min; MS(ES+) m/z 260 (M+H+MeCN).

(iii) {3-[(4-Methyl-5-phenyl-thiophene-2-carbonyl)-amino]-phenyl}-aceticacid ethyl ester

4-Methyl-5-phenyl-thiophene-2-carboxylic acid (25 mg, 0.11 mmol) wascoupled with ethyl ester (4) (20 mg, 0.11 mmol) following Method C. Thecrude residue was purified by column chromatography using 20% EtOAc inheptane to give the title compound.

Yield: 29 mg, 67%; LC/MS t_(r) 1.70 min; MS(ES+) m/z 380 (M+H).

(iv) {3-[(4-Methyl-5-phenyl-thiophene-2-carbonyl)-amino]-phenyl}-aceticacid (50)

The ethyl ester (29 mg, 0.08 mmol) was hydrolysed using Method H to givethe title compound.

Yield: 24 mg, 85%; LC/MS t_(r) 1.55 min; MS(ES+) m/z 352 (M+H); HPLCPurity: 84%; ¹H NMR (250 MHz, MeOD) δ 2.38 (s, 3H), 3.62 (s, 2H), 7.12(d, 1H), 7.30-7.60 (m, 7H), 7.64-7.67 (m, 1H), 7.77 (s, 1H).

(j) {3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (51)(i) [3-(5-Bromo-2-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester(78)

2-Fluoro-5-bromobenzoic acid (123 mg, 0.56 mmol) was coupled with ethylester (6) (100 mg, 0.56 mmol) following Method C to give the titlecompound.

Yield: 209 mg, 98%; LC/MS t_(r) 1.63 min; MS(ES+) m/z 380, 382 (M+H).

(ii) {3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid ethylester

[3-(5-Bromo-2-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester (78)(209 mg, 0.55 mmol) was coupled to phenylboronic acid using Method E,except that the reaction mixture was heated at 80° C. The crude residewas purified by column chromatography using 20% EtOAc in heptane to givethe title compound.

Yield: 98 mg, 47%; LC/MS t_(r) 1.71 min; MS(ES+) m/z 378 (M+H).

(iii) {3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (51)

The ethyl ester (98 mg, 0.26 mmol) was hydrolysed using Method H to givethe title compound.

Yield: 89 mg, 98%; LC/MS t_(r): 1.47 min; MS(ES+) m/z 350 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, MeOD) δ 3.55 (s, 2H), 7.16 (d, 1H),7.28-7.35 (m, 1H), 7.40-7.55 (m, 4H), 7.60-7.78 (m, 5H) 8.07-8.08 (m,1H).

(k) ({3-[(5-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (52)(i) [3-(3-Bromo-5-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester

3-Fluoro-5-bromobenzoic acid (123 mg, 0.56 mmol) was coupled with ethylester (6) (100 mg, 0.56 mmol) following Method C to give the titlecompound.

Yield: 209 mg, 98%; LC/MS t_(r) 1.52 min; MS(ES+) m/z 380, 382 (M+H).

(ii) {3-[(5-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid ethylester

[3-(3-Bromo-5-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester (209mg, 0.55 mmol) was coupled to phenylboronic acid using Method E, exceptthat the reaction mixture was heated at 80° C. The crude residue waspurified by column chromatography using 20% EtOAc in heptane to give thetitle compound.

Yield: 104 mg, 50%; LC/MS t_(r) 1.66 min; MS(ES+) m/z 378 (M+H).

(iii) {3-[(5-fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid (52)

The ethyl ester (104 mg, 0.28 mmol) was hydrolysed using Method H togive the title compound.

Yield: 91 mg, 95%; LC/MS t_(r) 1.42 min; MS(ES+) m/z 350 (M+H); HPLCPurity: 94%; ¹H NMR (250 MHz, MeOD) δ 3.60 (s, 2H), 7.14 (d, 1H),7.30-7.36 (m, 5H), 7.60 (s, 1H), 7.65-7.72 (m, 3H) 7.80-7.86 (m, 1H)7.97-8.00 (m, 1H).

(l) {3-[(2-Phenyl-1H-imidazole-5-carbonyl)-amino]-phenyl}-acetic acid(53) (i) {3-[(2-phenyl-1H-imidazole-5-carbonyl)-amino]-phenyl}aceticacid ethyl ester

2-Phenyl-1H-imidazole-5-carboxylic acid (105 mg, 0.56 mmol) was coupledwith ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give thetitle compound.

Yield: 116 mg, 59%; LC/MS t_(r) 1.19 min; MS(ES+) m/z 350 (M+H).

(ii) {3-[(2-Phenyl-1H-imidazole-5-carbonyl)-amino]-phenyl}-acetic acid(53)

The ethyl ester (50 mg, 0.14 mmol) was hydrolysed using Method H to givethe title compound.

Yield: 29 mg, 63%; LC/MS t_(r) 1.39 min; MS(ES+) m/z 322 (M+H); HPLCPurity: 89%; ¹H NMR (250 MHz, MeOD) δ 3.66 (s, 2H), 7.10 (d, 1H),7.31-7.37 (m, 1H), 7.43-7.56 (m, 3H), 7.67-7.68 (m, 2H), 7.87 (s, 1H),7.97-8.00 (m, 2H).

(m) {3-[(2-Phenyl-thiazole-4-carbonyl)-amino]-phenyl}-acetic acid (54)(i) 2-Amino-thiazole-4-carboxylic acid ethyl ester hydrobromide salt

Thiourea (1.5 g, 20 mmol) and ethyl bromopyruvate (2.8 ml, 22 mmol) wereheated at 100° C. for 1 h. The reaction was cooled and acetone (10 ml)was added. The mixture was then filtered to give a yellow/brown solidand the crude material was crystallised from hot ethanol (20 ml) to givethe title compound as the HBr salt (2.63 g). The liquor was concentratedand recrystallised from hot EtOH (5 ml) to give further product (0.63g).

Yield: 3.26 g, 64%; LC/MS t_(r) 0.67 min; MS(ES+) m/z 173 (M+H); ¹H NMR(400 MHz, MeOD) δ 1.42 (t, 3H), 4.43 (q, 2H), 7.74 (s, 1H).

(ii) 2-Chloro-thiazole-4-carboxylic acid ethyl ester

2-Amino-thiazole-4-carboxylic acid ethyl ester hydrobromide salt (506mg, 2 mmol) was converted to the free base by partitioning betweenaqueous saturated K₂CO₃ solution and EtOAc. The organic layer was washedwith brine, dried (Na₂SO₄), filtered and the solvent removed in vacuo togive the free base (306 mg, 89%).

The free based 2-amino-thiazole-4-carboxylic acid ethyl ester (306 mg,1.78 mmol) and CuCl (238 mg, 2.4 mmol) were suspended in conc. HCl (8ml) and the mixture cooled on a salt/ice bath. A pre-cooled solution ofNaNO₂ (166 mg, 2.4 mmol) in water (2 ml) was added over a period of 10min. The mixture was allowed to warm to room temperature over 1 h andwas stirred for a further 1 h. Water was added and the aqueous layerextracted with EtOAc (3×10 ml). The combined EtOAc layers were washedwith brine, dried (Na₂SO₄), filtered and the solvent removed in vacuo togive the title compound.

Yield: 251 mg, 74%; LC/MS t_(r) 1.06 min; MS(ES+) m/z 192, 194 (M+H); ¹HNMR (250 MHz, CDCl₃) δ 1.41 (t, 3H), 4.43 (q, 2H), 8.08 (s, 1H).

(iii) 2-Chloro-thiazole-4-carboxylic acid (79)

The ethyl ester (120 mg, 0.63 mmol) was hydrolysed using Method H togive the title compound.

Yield: 75 mg, 73%; LC/MS t_(r) 0.77 min; MS(ES+) m/z 164, 166 (M+H).

(iv) {3-[(2-Chloro-thiazole-4-carbonyl)-amino]-phenyl}-acetic acid ethylester

2-Chloro-thiazole-4-carboxylic acid (79) (70 mg, 0.43 mmol) was coupledwith ethyl ester (6) (77 mg, 0.43 mmol) following Method C to give thetitle compound.

Yield: 114 mg, 82%; LC/MS t_(r) 1.44 min; MS(ES+) m/z 325, 327 (M+H).

(v) {3-[(2-Phenyl-thiazole-4-carbonyl)-amino]-phenyl}-acetic acid ethylester

{3-[(2-Chloro-thiazole-4-carbonyl)-amino]-phenyl}-acetic acid ethylester (114 mg, 0.35 mmol) was coupled to phenylboronic acid using MethodE, except that the reaction mixture was heated for 140 min. The cruderesidue was purified by column chromatography using 33% EtOAc in heptaneto give the title compound.

Yield: 37 mg, 29%; LC/MS t_(r) 1.64 min; MS(ES+) m/z 367 (M+H).

(vi) {3-[(2-Phenyl-thiazole-4-carbonyl)-amino]-phenyl}-acetic acid (54)

The ethyl ester (37 mg, 0.10 mmol) was hydrolysed using Method H to givethe title compound.

Yield: 23 mg, 67%; LC/MS t_(r) 1.62 min; MS(ES+) m/z 339 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, MeOD) δ 3.68 (s, 2H), 7.15 (d, 1H),7.36-7.40 (m, 1H), 7.54-7.58 (m, 3H), 7.74-7.75 (m, 2H), 8.15-8.16 (m,2H), 8.35 (s, 1H).

(n) 3-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid (57) (i)5-Bromo-furan-2-carboxylic acid methyl ester (55)

5-Bromo-furan-2-carboxylic acid (2 g, 10.5 mmol) was esterified withMeOH using Method B to give the title compound.

Yield: 1.54 g, 72%; LC-MS t_(r) 1.24 min; MS(ES+) m/z 205, 207 (M+H).

(ii) 5-Phenyl-furan-2-carboxylic acid (56)

5-Bromo-furan-2-carboxylic acid methyl ester (5) (205 mg, 1 mmol) wascoupled to phenylboronic acid (146 mg, 1.2 mmol) using Method E exceptthat once the reaction was complete, the solvents were removed in vacuo.The crude residue was re-dissolved in EtOAc (10 ml) and 1M NaOH (20 ml)was added. The aqueous layer was extracted with EtOAc (3×10 ml), and theorganic layer was discarded. The aqueous layer was acidified to pH 1with conc. HCl, and extracted with EtOAc (3×10 ml). The combined organiclayers were dried (MgSO₄), filtered, and the solvent removed in vacuo togive the title compound.

Yield: 190 mg, 100%; LC-MS t_(r)1.23 min; MS(ES+) m/z 189 (M+H).

(iii) 3-[9H-Fluoren-9-ylmethoxycarbonylamino)-methyl]-benzoic acidmethyl ester

3-[(9H-Fluoren-9-ylmethoxycarbonylamino)-methyl]-benzoic acid (200 mg,0.54 mmol) was esterified with MeOH using Method B to give the titlecompound.

Yield: 193 mg, 93%; LC-MS t_(r)1.64 min; MS(ES+) m/z 388 (M+H).

(iv) 3-Aminomethyl-benzoic acid methyl ester

A 20% solution of piperidine in DMF (5 ml) was added to3-[(9H-Fluoren-9-ylmethoxycarbonylamino)-methyl]-benzoic acid methylester (193 mg, 0.5 mmol) and the reaction was stirred at roomtemperature for 30 min. Water (10 ml) was added to the crude reactionmixture, followed by 1M HCl (10 ml). The aqueous layer was washed withEtOAc (3×10 ml) then basified to pH 9 with saturated NaHCO₃. The basiclayer was extracted with EtOAc (3×10 ml) and the aqueous layer wasevaporated down to a small volume, then further extracted with EtOAc(5×10 ml). The combined organic layers were dried (MgSO₄), filtered andthe solvent evaporated in vacuo to give the title compound.

Yield: 17 mg, 21%; LC-MS t_(r)0.77 min; MS(ES+) m/z 166 (M+H).

(v) 3-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid methylester

5-Phenyl-furan-2-carboxylic acid (6) (17 mg, 0.10 mmol) was coupled to3-aminomethyl-benzoic acid methyl ester (19.4 mg, 0.10 mmol) usingMethod D to give the title compound

Yield: 18 mg, 52%; LC-MS t_(r)1.90 min; MS(ES+) m/z 336 (M+H).

(vi) 3-{[(5-Phenyl-furan-2-carbonyl)-amino]-methyl}-benzoic acid (57)

The ester (10 mg, 0.03 mmol) was dissolved in THF (0.1 ml) and NaOH (20mg, 0.5 mmol) was dissolved in H₂O (0.1 ml). The solutions were combinedand stirred at room temperature for 6 h. Further NaOH (50 mg, 1.25 mmol)was added and the reaction was stirred overnight. The THF was removedunder a stream of N₂ and the aqueous layer was acidified to pH 3 with 2MHCl before extracting with EtOAc (3×1 ml). The combined organic layerswere dried (MgSO₄), filtered and the solvent removed in vacuo to givethe title compound as a white solid.

Yield: 5 mg, 52%; LC-MS t_(r)1.76 min; MS(ES+) m/z 322 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD) δ 4.53 (s, 2H), 6.82 (d, 1H), 7.12(d, 1H), 7.24 (t, 1H), 7.30-7.37 (m, 3H), 7.51 (d, 1H), 7.76 (d, 2H),7.82 (d, 1H), 7.95 (s, 1H).

(o) 5-[(5-Phenyl-furan-2-carbonyl)-amino]-1H-indole-2-carboxylic acid(59) (i) 5-Amino-1H-indole-2-carboxylic acid ethyl ester (58)

5-Nitro-1H-indole-2-carboxylic acid ethyl ester (500 mg, 2.1 mmol) wasreduced using Method I to give the title compound.

Yield: 433 mg, 100%; LC-MS t_(r) 0.84 min; MS(ES+) m/z 205 (M+H).

(ii) 5-[(5-Phenyl-furan-2-carbonyl)-amino]-1H-indole-2-carboxylic acidethyl ester

5-Phenyl-furan-2-carboxylic acid (56) (35 mg, 0.19 mmol) was coupled to5-amino-1H-indole-2-carboxylic acid ethyl ester (42 mg, 0.20 mmol) usingMethod D to give the title compound.

Yield: 10 mg, 14%; LC-MS t_(r)1.55 min; MS(ES+) m/z 375 (M+H).

(iii) 5-[(5-Phenyl-furan-2-carbonyl)-amino]-1H-indole-2-carboxylic acid(59)

The ester (10 mg, 0.027 mmol) was dissolved in THF (0.5 ml) and water (2ml). LiOH.H₂O (11 mg, 0.27 mmol) was then added as a solid. Theresulting solution was stirred for 48 h at room temperature and thenheated to 40° C. for 3 h with a few drops of MeOH. The THF was removedin vacuo and the basic solution was extracted with EtOAc (3×1 ml). Theaqueous layer was acidified to pH 1 with conc. HCl and then extractedwith EtOAc (3×1 ml). The combined organic layers were evaporated invacuo to give the title compound.

Yield: 5.4 mg, 58%; LC/MS t_(r) 1.34 min; MS(ES+) m/z 347 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD) δ 6.83-6.89 (m, 1H), 7.03-7.07 (m,1H), 7.20-7.29 (m, 2H), 7.30-7.38 (m, 3H), 7.40-7.45 (m, 1H), 7.78-7.85(m, 2H), 7.90 (s, 1H).

(p) 3-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-acrylic acid (61)(i) 3-(3-Amino-phenyl)-acrylic acid ethyl ester (60)

3-(3-Nitro-phenyl)-acrylic acid ethyl ester (500 mg, 2.3 mmol) wasreduced using Method J to give the title compound.

Yield: 430 mg, 100%; LC-MS t_(r)0.92 min; MS(ES+) m/z 192 (M+H).

(ii) 3-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-acrylic acid ethylester

5-Phenyl-furan-2-carboxylic acid (56) (35 mg, 0.19 mmol) was coupled to3-(3-amino-phenyl)-acrylic acid ethyl ester (60) (39 mg, 0.20 mmol)using Method D to give the title compound.

Yield: 13 mg, 18%; LC-MS t_(r)1.65 min; MS(ES+) m/z 362 (M+H).

(iii) 3-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-acrylic acid (61)

The ester (13 mg, 0.036 mmol) was dissolved in THF (0.5 ml) and water (2ml). LiOH.H₂O (15 mg, 0.36 mmol) was then added as a solid and theresulting solution was stirred at room temperature for 18 h. The THF wasremoved in vacuo and the basic solution was extracted with EtOAc (3×1ml). The aqueous layer was acidified to pH 1 with conc. HCl and thenextracted with EtOAc (3×1 ml). The combined organic layers wereevaporated in vacuo to give the title compound.

Yield: 3.4 mg, 28%; LC/MS t_(r) 1.34 min; MS(ES+) m/z 334 (M+H); HPLCPurity: 94%; ¹H NMR (400 MHz; MeOD) δ 6.43 (d, 1H), 6.92 (d, 1H),7.25-7.41 (m, 6H), 7.59 (d, 1H), 7.72 (d, 1H), 7.86 (m, 2H), 7.91 (s,1H).

(q) 3-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-propionic acid (62)(i) 3-(3-Amino-phenyl)-propionic acid methyl ester

3-(3-Amino-phenyl)-propionic acid (495 mg, 3 mmol) was esterified withMeOH using Method A, except that the residue was partitioned betweenEtOAc (10 ml) and saturated aqueous NaHCO₃ (10 ml). The organic layerwas dried (MgSO₄), filtered and evaporated in vacuo to give the titlecompound.

Yield: 448 mg, 83%; LC-MS t_(r) 0.78 min; MS(ES+) m/z 180 (M+H).

(ii) 3-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-propionic acidmethyl ester

5-Phenyl-furan-2-carboxylic acid (56) (40 mg, 0.21 mmol) was coupled to3-(3-amino-phenyl)-propionic acid methyl ester (41 mg, 0.23 mmol) usingMethod D to give the title compound.

Yield: 38 mg, 52%; LC-MS t_(r)1.51 min; MS(ES+) m/z 350 (M+H).

(iii) 3-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenyl}-propionic acid(62)

The ester (38 mg, 0.11 mmol) was dissolved in THF (1.5 ml) and NaOH (76mg, 1.9 mmol) was dissolved in H₂O (1 ml). The solutions were combinedand stirred at room temperature for 1 h. The THF was removed in vacuoand the aqueous layer was extracted with EtOAc (3×1 ml). The aqueouslayer was then acidified to pH 1 with 1M HCl and then extracted withEtOAc (3×1 ml). The combined organic layers were dried (MgSO₄),filtered, and the solvent removed in vacuo to give the title compound.

Yield: 31 mg, 86%; LC/MS t_(r) 1.39 min; MS(ES+) m/z 336 (M+H); HPLCPurity: 93%; ¹H NMR (250 MHz; CDCl₃) δ 2.71 (t, 2H), 3.01 (t, 2H), 6.81(d, 1H), 7.01 (d, 1H), 7.22-7.58 (m, 7H), 7.74 (d, 2H), 8.08 (s, 1H).

(r) 6-[(5-Phenyl-furan-2-carbonyl)-amino]-naphthalene-2-carboxylic acid(63) (i) 6-Amino-naphthalene-2-carboxylic acid methyl ester

6-Amino-naphthalene-2-carboxylic acid (561 mg, 3 mmol) was esterifiedwith MeOH using Method B to give the title compound.

Yield: 360 mg, 59%; MS(ES+) m/z 203 (M+H).

(ii) 6-[(5-Phenyl-furan-2-carbonyl)-amino]-naphthalene-2-carboxylic acidmethyl ester

5-Phenyl-furan-2-carboxylic acid (56) (50 mg, 0.26 mmol) was coupled to6-amino-naphthalene-2-carboxylic acid methyl ester (53 mg, (0.26 mmol)using Method C to give the title compound.

Yield: 17 mg, 17%; MS(ES+) m/z 372 (M+H).

(iii) 6-[(5-Phenyl-furan-2-carbonyl)-amino]-naphthalene-2-carboxylicacid (63)

The ester (17 mg, 0.046 mmol) was dissolved in THF (1.5 ml) and MeOH (2ml). NaOH (34 mg, 0.85 mmol) was dissolved in H₂O (1 ml). The solutionswere combined and stirred at room temperature for 3.5 h. Further NaOH(34 mg, 0.85 mmol) was then added and the reaction mixture was stirredfor 18 h at room temperature. The THF was removed under a stream of N₂,then MeOH (2 ml) was added and the resulting solution was heated at 40°C. for 2 h. The reaction was cooled to room temperature and stirred for18 h. The MeOH was removed under a stream of N₂ and the aqueous layerextracted with EtOAc (3×1 ml). The aqueous layer was then acidified topH 1 with 1M HCl and extracted with EtOAc (3×1 ml). The combined organiclayers were dried (MgSO₄), filtered, and the solvents removed in vacuoto give the title compound.

Yield: 15 mg, 86%; LC/MS t_(r) 1.53 min; MS(ES+) m/z 378 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz; d-DMSO) δ 7.22 (s, 1H), 7.40-7.48 (m,1H), 7.50-7.57 (m, 3H), 7.92-8.02 (m, 5H), 8.13 (d, 1H), 8.55 (d, 2H),10.52 (s, 1H), 13.01 (s, 1H).

(s) (3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (66) (i) (3-Acetylamino-phenoxy)-acetic acid ethyl ester

To a solution of N-(3-hydroxy-phenyl)-acetamide (0.5 g, 3.3 mmol) inacetone (5 ml) was added K₂CO₃ (0.46 g, 3.3 mmol), ethyl bromoacetate(0.67 g, 4.0 mmol) and 10 4 A molecular sieves. The reaction mixture wasthen heated in the microwave for 1 h at 100° C. (150 W, 200 psi). Thereaction mixture was filtered and the acetone layer evaporated in vacuo.This residue was dissolved in EtOAc (10 ml) and washed with 2M KOH (5ml×2). The organic layer was dried (Na₂SO₄), filtered and the solventremoved in vacuo to give the title compound as a colourless oil whichsolidified upon standing.

Yield: 700 mg, 89%; LC/MS t_(r) 1.04 min; MS(ES+) m/z 238 (M+H).

(ii) (3-Amino-phenoxy)-acetic acid

The ester (0.25 g, 1 mmol) was suspended in 1.2 M HCl and heated to 100°C. for 80 min. The water was removed in vacuo to give the title compoundas the hydrochloride salt.

Yield: 170 mg, 83%; LC/MS t_(r) 0.17 and 0.56 min; MS(ES+) m/z 168(M+H).

(iii) (3-Amino-phenoxy)-acetic acid ethyl ester (64)

The carboxylic acid (100 mg, 0.6 mmol) was suspended in EtOH (1 ml) at0° C. and SOCl₂ (78 mg, 0.7 mmol) was added dropwise. The reactionmixture was allowed to warm to room temperature and stirred for 18 h.The solvent was removed in vacuo to give the title compound as thehydrochloride salt.

Yield: 139 mg, 100%; LC/MS t_(r) 0.79 min; MS(ES+) m/z 196 (M+H); ¹H NMR(400 MHz; CDCl₃) δ 1.26 (t, 3H), 4.23 (q, 2H), 4.58 (s, 2H), 6.86 (d,1H), 7.15 (s, 2H), 7.25 (t, 1H).

(iv) 5-(3-Chloro-phenyl)-furan-2-carboxylic acid (65)

5-Bromo-2-furoic acid (1 g, 5.8 mmol) was coupled to3-chloro-phenylboronic acid (683 g, 4.4 mmol) acid using Method F togive the title compound.

Yield: 510 mg, 52%; LC/MS t_(r) 1.24 min; MS(ES+) m/z 223, 225 (M+H).

(v) (3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid ethyl ester

Carboxylic acid (65) (67 mg, 0.3 mmol) was coupled to ethyl ester (64)(58 mg, 0.25 mmol) using Method C. The crude residue was purified bycolumn chromatography eluting with a stepped gradient of 10-20% EtOAc inheptane to give the title compound.

Yield: 75 mg, 75%; LC/MS t_(r) 1.65 min; MS(ES+) m/z 400, 402 (M+H).

(vi) (3-{[5-(3-Chloro-Thenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (66)

The ester (64 mg, 0.16 mmol) was dissolved in MeOH (1.5 ml), and asolution of NaOH (128 mg, 3.2 mmol) in water (0.5 ml) was added. Thereaction mixture was stirred for 1 h at room temperature before the MeOHwas removed in vacuo. The aqueous layer was washed with EtOAc (2×2 ml)and then acidified with 2M HCl until a white precipitate formed. Thiswas then extracted with EtOAc (2 ml). The organic layer was dried(Na₂SO₄), filtered and the solvent removed in vacuo to give the titlecompound.

Yield: 30 mg, 50%; LC/MS t_(r) 1.45 min; MS(ES+) m/z 372, 374 (M+H);HPLC Purity: 99%; ¹H NMR (400 MHz; DMSO) δ 4.24 (s, 2H), 6.69 (d, 1H),7.31 (t, 1H), 7.42 (m, 3H), 7.55 (m, 2H), 7.64 (t, 1H), 8.05 (d, 1H),8.21 (s, 1H), 10.38 (s, 1H).

(t)(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (68) (i) 5-(3,5-Dichloro-phenyl)-furan-2-carboxylic acid (67)

5-Bromo-2-furoic acid (1 g, 4.8 mmol) was coupled to3,5-dichloro-phenylboronic acid (833 g, 4.4 mmol) acid using Method F togive the title compound.

Yield: 500 mg, 44%; LC/MS t_(r) 1.48 min; MS(ES+) m/z 257, 259 (M+H).

(ii)(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid ethyl ester

Carboxylic acid (67) (77 mg, 0.3 mmol) was coupled to ethyl ester (9)(58 mg, 0.25 mmol) using Method C. The crude residue was purified bycolumn chromatography eluting with 10% EtOAc in heptane to give thetitle compound.

Yield: 109 mg, 100%; LC/MS t_(r) 1.78 min; MS(ES+) m/z 434, 436 (M+H).

(iii)(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (68)

The ester (70 mg, 0.16 mmol) was dissolved in MeOH (1.5 ml) and asolution of NaOH (140 mg, 3.5 mmol) in water (0.5 ml) was added. Thereaction mixture was stirred for 1 h at room temperature and the MeOHwas removed in vacuo. The aqueous layer was washed with EtOAc (2×2 ml)and then acidified with 2M HCl until a white precipitate formed. Thiswas then extracted with EtOAc (2 ml). The organic layer was dried(Na₂SO₄), filtered and the solvent removed in vacuo to give the titlecompound.

Yield: 40 mg, 61%; LC/MS t_(r) 1.58 min; MS(ES+) m/z 406, 408 (M+H);HPLC Purity: 99%; ¹H NMR (400 MHz; DMSO) δ 4.20 (s, 2H), 6.65 (d, 1H),7.25 (t, 1H), 7.35 (s, 2H), 7.47 (d, 2H), 7.69 (s, 1H), 8.15 (s, 2H).

(u) 3-(3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (69) (i)3-(3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic acidethyl ester

Carboxylic acid (65) (58 mg, 0.26 mmol) was coupled to ethyl ester (60)(50 mg, 0.26 mmol) using Method C. The crude residue was purified bycolumn chromatography eluting with a stepped gradient of 10-15% EtOAc inheptane to give the title compound.

Yield: 67 mg, 65%; LC/MS t_(r) 1.72 min; MS(ES+) m/z 396, 398 (M+H).

(ii) 3-(3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (69)

The ester (67 mg, 0.17 mmol) was dissolved in THF (1 ml) and water (0.25ml). To this was added LiOH.H₂O (20 mg, 0.48 mmol) and the reaction wasstirred for 2 h at room temperature. The THF was removed in vacuo andthe aqueous layer was washed twice with EtOAc (2×2 ml) then acidifiedwith 2M HCl until a white precipitate formed. This was then extractedwith EtOAc (2 ml). The organic layer was dried (Na₂SO₄), filtered andthe solvent removed in vacuo to give the title compound.

Yield: 23 mg, 37%; LC/MS t_(r) 1.51 min; MS(ES+) m/z 367, 369 (M+H);HPLC Purity: 98%; ¹H NMR (400 MHz; DMSO) δ 6.41 (d, 1H), 7.24 (d, 1H),7.36 (m, 4H), 7.45 (t, 1H), 7.51 (d, 1H), 7.74 (m, 1H), 7.87 (m, 1H),7.92 (s, 1H), 8.04 (t, 1H), 10.25 (s, 1H).

(v)3-(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (70) (i)3-(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

Carboxylic acid (67) (67 mg, 0.26 mmol) was coupled to ethyl ester (60)(50 mg, 0.26 mmol) using Method C. The crude residue was purified bycolumn chromatography eluting with 10% EtOAc in heptane to give thetitle compound.

Yield: 90 mg, 80%; LC/MS t_(r) 1.84 min; MS(ES+) m/z 430, 432 (M+H).

(ii)3-(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (70)

The ester (90 mg, 0.21 mmol) was dissolved in THF (1 ml) and water (0.25ml). To this was added LiOH.H₂O (30 mg, 0.71 mmol) and the resultingsolution was stirred for 2 h at room temperature. The THF was removed invacuo and the aqueous layer was washed twice with EtOAc (2×2 ml) thenacidified with 2M HCl until a white precipitate formed. This was thenextracted with EtOAc (2 ml). The organic layer was dried (Na₂SO₄),filtered and the solvent removed in vacuo to give the title compound.

Yield: 41 mg, 48%; LC/MS t_(r) 1.63 min; MS(ES+) m/z 402, 404 (M+H);HPLC Purity: 98%; ¹H NMR (400 MHz; DMSO) δ 6.42 (d, 1H), 7.37 (m, 4H),7.51 (d, 1H), 7.55 (t, 1H), 7.73 (d, 1H), 7.91 (s, 1H), 8.04 (d, 2H),10.29 (s, 1H).

(x) 3-(3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (71) (i) 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid

4-Fluoro-phenylboronic acid (611 mg, 4.4 mmol) was coupled to5-bromo-2-furoic acid (1 g, 4.8 mmol) using Method F to give the titlecompound.

Yield: 350 mg, 39%; LC/MS t_(r) 1.24 min; MS(ES+) m/z 207 (M+H).

(ii) 3-(3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

5-(4-Fluoro-phenyl)-furan-2-carboxylic acid (54 mg, 0.26 mmol) wascoupled to ethyl ester (60) (50 mg, 0.26 mmol) using Method C. The cruderesidue was purified by column chromatography eluting with 10% EtOAc inheptane to give the title compound.

Yield: 98 mg, 100%; LC/MS t_(r) 1.67 min; MS(ES+) m/z 380 (M+H).

(iii)3-(3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic acid(71)

The ester (109 mg, 0.29 mmol) was dissolved in THF (0.4 ml) and water(0.1 ml). To this was added LiOH.H₂O (126 mg, 3.1 mmol) and theresulting solution was stirred for 2 h at room temperature. The THF wasremoved in vacuo and the aqueous layer was washed twice with EtOAc (2×2ml) then acidified with 2M HCl until a white precipitate formed. Thiswas then extracted with EtOAc (2 ml). The combined organic layers weredried (Na₂SO₄), filtered and the solvent removed in vacuo to give thetitle compound.

Yield: 48 mg, 47%; LC/MS t_(r) 1.42 min; MS(ES+) m/z 352 (M+H); HPLCPurity: 98%; ¹H NMR (400 MHz; DMSO) δ 6.47 (d, 1H), 7.18 (d, 1H), 7.23(d, 1H), 7.29 (d, 1H), 7.41 (q, 3H), 7.54 (d, 1H), 7.80 (d, 1H), 7.93(s, 1H), 8.11 (q, 2H), 10.42 (s, 1H).

(y)5-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-1H-indole-2-carboxylicacid (72) (i)5-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-1H-indole-2-carboxylicacid ethyl ester

5-(3-Chloro-phenyl)-furan-2-carboxylic acid (65) (54 mg, 0.24 mmol) wascoupled to ethyl ester (58) (50 mg, 0.24 mmol) using Method C. The cruderesidue was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 42 mg, 43%; LC/MS t_(r) 1.64 min; MS(ES+) m/z 409, 411 (M+H);HPLC Purity: 92%.

(ii)5-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-1H-indole-2-carboxylicacid (72)

The ester (42 mg, 0.10 mmol) was dissolved in THF (0.2 ml) and water(0.05 ml). To this was added LiOH.H₂O (42 mg, 1 mmol) and the resultingsolution was stirred for 2 h at room temperature then at 35° C. for 2 h.The THF was removed under a stream of N₂ and the aqueous layer acidifiedwith 2M HCl until a white precipitate formed. This was then extractedwith EtOAc (2 ml). The organic layer was dried (Na₂SO₄), filtered, andthe solvent removed in vacuo to give the title compound which wasre-suspended in hot DCM (1.5 ml), then hot MeCN (1.5 ml), filtered, anddried in vacuo.

Yield: 30 mg, 79%; LC/MS t_(r) 1.46 min; MS(ES+) m/z 380, 382 (M+H);HPLC Purity: 97%; ¹H NMR (360 MHz; DMSO): δ 6.55 (s, 1H), 7.22-7.42 (m,6H), 7.48 (t, 1H), 7.80 (s, 1H), 7.91 (d, 1H), 8.10 (s, 1H), 10.08 (s,1H), 11.07 (s, 1H).

Example 8 (a) 5-Phenyl-furan-2-carboxylic acid(3-carbamoylmethyl-phenyl)-amide (73)

The carboxylic acid (10) (50 mg, 0.15 mmol) was coupled to NH₄OH (0.01ml, 0.15 mmol) using Method C. The crude compound was purified by columnchromatography, eluting with a stepped gradient of 80-100% EtOAc inheptane to give the title compound.

Yield: 15 mg, 31%; LC/MS t_(r) 1.23 min; MS(ES+) m/z 321 (M+H); HPLCPurity: 95%; ¹H NMR (400 MHz; CDCl₃) δ 3.44 (m, 2H), 6.98 (brs, 2H),7.08 (d, 1H), 7.24 (d, 1H), 7.35 (t, 1H), 7.46 (t, 2H), 7.56 (t, 2H),7.70 (s, 1H), 7.74 (d, 1H), 8.04 (d, 2H), 10.23 (s, 1H).

(b) Phenyl-furan-2-carboxylic acid [3-(2-hydroxy-ethyl)-phenyl]-amide(74)

The carboxylic acid (10) (50 mg, 0.15 mmol) was dissolved in anhydrousTHF (0.1 ml) and placed under an atmosphere of N₂. The solution wascooled to −78° C. using acetone/dry ice and stirred for 10 min. LiAlH₄(1M in THF) was added dropwise (0.31 ml, 0.31 mmol) and the resultingsolution was stirred for 10 min at −78° C., then allowed to warm to roomtemperature and stirred for a further 2 h. After cooling to 5° C. usingice/water, the reaction mixture was quenched by dropwise addition ofwater (1 ml) then neutralised to pH 7 with 1M NaOH and extracted withEtOAc (2×1 ml). The combined organic layers were dried (Na₂SO₄),filtered and the solvent removed in vacuo. The crude residue waspurified by column chromatography, eluting in 60% EtOAc in heptane togive the title compound.

Yield: 34 mg, 70; LC/MS t_(r) 1.35 min; MS(ES+) m/z 308 (M+H); HPLCPurity: 92%; ¹H NMR (400 MHz; CDCl₃) δ 2.90 (t, 2H), 3.91 (t, 2H), 6.80(d, 1H), 7.05 (d, 1H), 7.03 (d, 1H), 7.29-7.41 (m, 3H), 7.46 (t, 2H),7.58 (d, 2H), 7.76 (d, 2H), 8.09 (s, 1H).

(c) 5-Phenyl-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (75) (i)(3-Amino-phenyl)-acetonitrile (80)

A solution of 3-nitrophenyl acetonitrile (500 mg, 3.1 mmol) in 5% AcOH(10 ml) was heated to 80° C. Iron powder (1.5 g, 27 mmol) was then addedand the resulting mixture stirred for 2 h. The reaction mixture wasfiltered through celite and the filter cake washed with MeCN (4×50 ml).The combined MeCN layers were evaporated in vacuo and the residue wasre-dissolved in EtOAc (30 ml) followed by 2M HCl (30 ml). The aqueouslayer was separated, basified to pH 10 with 6M NaOH, and extracted withEtOAc (3×80 ml). The combined organic layers were dried (MgSO₄),filtered and the solvent removed in vacuo to give the title compound.

Yield: 140 mg, 34%; ¹H NMR (400 MHz, CDCl₃): δ 3.65 (s, 2H), 3.75 (s,2H), 6.60-6.70 (m, 3H), 7.15 (t, 1H).

(ii) 5-Phenyl-furan-2-carboxylic acid (3-cyanomethyl-phenyl)-amide

5-Phenyl-2-furoic acid (56) (223 mg, 1.2 mmol) was coupled to3-aminophenyl acetonitrile (80) (157 mg, 1.19 mmol), using Method C. Thecrude residue was purified by column chromatography, eluting in 17%EtOAc in heptane to give the title compound.

Yield: 70 mg, 19%; LC/MS t_(r) 1.47 min; MS(ES+) m/z 303 (M+H).

(iii) 5-Phenyl-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide

To a solution of 5-phenyl-furan-2-carboxylic acid(3-cyanomethyl-phenyl)-amide (70 mg, 0.23 mmol) in toluene (3 ml) wasadded Me₃SnN₃ (56 mg, 0.28 mmol). After heating to reflux for 18 h,additional Me₃SnN₃ (56 mg, 0.28 mmol) and toluene (2 ml) were added andthe reaction was heated to reflux for a further 18 h. After this time,2M NaOH (2 ml) and hexane (2 ml) were added to the reaction mixture andstirred for 10 min. Water (1 ml) was added and the organic layerseparated. EtOAc (2 ml) was added to the aqueous layer and the solutionstirred for 2 min before the organic layer was separated. The combinedorganic layers were discarded. The aqueous layer was then acidified topH 5 with 2M HCl then EtOAc (2.5 ml) was added and the solution stirredfor 10 min after which time the organic layer was separated. EtOAc (2.5ml) was added to the aqueous layer and the solution stirred for 1 hour.The EtOAc layer was separated and these combined organic layers wereevaporated in vacuo to give the title compound.

Yield: 16 mg, 20%; LC/MS t_(r) 1.31 min; MS(ES+) m/z 346 (M+H); HPLCPurity: 98%; NMR (400 MHz, DMSO): δ 4.2 (s, 2H), 7.1 (d, 1H), 7.25 (s,1H), 7.35 (t, 1H), 7.4-7.49 (m, 2H), 7.55 (t, 2H), 7.65 (s, 1H), 7.75(d, 1H), 8.0 (d, 2H), 10.25 (s, 1H).

(d) 5-Phenyl-furan-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide(177) (i) 5-Phenyl-furan-2-carboxylic acid (3-cyano-phenyl)-amide

Carboxylic acid (56) (150 mg, 0.80 mmol) was coupled to3-amino-benzonitrile (94 mg, 0.80 mmol) using Method C. The residue waspurified by column chromatography eluting with 17% EtOAc in heptane togive the title compound.

Yield: 80 mg, 35%; LC/MS t_(r) 1.51 min; MS(ES+) m/z 289 (M+H).

(ii) 5-Phenyl-furan-2-carboxylic acid[3-(1H-tetrazol-5-yl)-phenyl]-amide (177)

The nitrile (80 mg, 0.28 mmol) was reacted with Me₃SnN₃ using Method K.The solid was then re-dissolved in EtOAc (2 ml) and 2M NaOH (2 ml). Thelayers were separated and the aqueous layer was acidified to pH 5 with2M HCl and extracted with EtOAc (2 ml). The combined organic layers wereevaporated in vacuo and the residue triturated with TBME (2×2 ml). Thesolid was dissolved in MeOH (1.5 ml) and washed with heptane (2×2 ml).MeOH was removed in vacuo to give the title compound. Yield: 15 mg, 16%;LC/MS t_(r) 1.42 min; MS(ES+) m/z 332 (M+H); HPLC Purity: 98%; ¹H NMR(400 MHz, DMSO): δ 7.07 (d, 1H), 7.19-7.42 (m, 5H), 7.60 (d, 1H), 7.69(d, 1H), 7.89 (d, 2H), 8.18-8.20 (m, 1H), 10.13 (s, 1H).

(e) 5-(3-Chloro-phenyl)-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (81) (i){3-[5-(3-Chloro-phenyl)-furan-2-carbonyl]-phenyl}-acetonitrile

Carboxylic acid (65) (127 mg, 0.57 mmol) was coupled to aniline (80) (75mg, 0.57 mmol) using Method C. The crude residue was purified by columnchromatography eluting with 17% EtOAc in heptane to give the titlecompound.

Yield: 65 mg, 34%; LC/MS t_(r) 1.57 min; MS(ES+) m/z 337, 339 (M+H).

(ii) 5-(3-Chloro-phenyl)-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (81)

The nitrile (65 mg, 0.19 mmol) was reacted with Me₃SnN₃ using Method K.The solid was re-dissolved in MeOH (2.5 ml) and washed with heptane (5×3ml). The product was further purified by column chromatography elutingwith a stepped gradient of 10-100% EtOAc in heptane to give the titlecompound.

Yield: 1.2 mg, 2%; LC/MS t_(r) 1.48 min; MS(ES+) m/z 380, 382 (M+H);HPLC Purity: 98%; ¹H NMR (400 MHz, DMSO): δ 4.38 (s, 2H), 7.11 (d, 1H),7.35-7.57 (m, 3H), 7.49-7.53 (m, 1H), 7.56-7.62 (t, 1H), 7.69 (s, 1H),7.79 (d, 1H), 8.00 (d, 1H), 8.19 (s, 1H), 10.32 (s, 1H).

(f) 5-(3,5-Dichloro-phenyl)-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (82) (i)5-(3,5-Dichloro-phenyl)-furan-2-carboxylic acid(3-cyanomethyl-phenyl)-amide

Carboxylic acid (67) (62 mg, 0.24 mmol) was coupled to aniline (80) (32mg, 0.24 mmol) using Method C. After work-up, the solid wasrecrystallised from MeCN (3 ml) to give the title compound.

Yield: 63 mg, 71%; LC/MS t_(r) 1.73 min; MS(ES+) m/z 371, 373 (M+H).

(ii) 5-(3,5-Dichloro-phenyl)-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (82)

The nitrile (63 mg, 0.17 mmol) was reacted with Me₃SnN₃ using Method K.The residue was purified by column chromatography, flushing with heptane(200 ml) and eluting with 50% MeOH in EtOAc. The solid was thentriturated with MeOH (3 ml) to give the title compound.

Yield: 4.2 mg, 6%; LC/MS t_(r) 1.53 min; MS(ES+) m/z 414, 416 (M+H);HPLC Purity: 92%; ¹H NMR (400 MHz, DMSO): δ 4.48 (s, 2H), 7.21 (d, 1H),7.43-7.60 (m, 3H), 7.75-7.81 (m, 2H), 7.88 (d, 1H), 8.26 (s, 2H), 10.45(s, 1H).

(g) 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (85) (i)5-Bromo-furan-2-carboxylic acid (3-cyanomethyl-phenyl)-amide (83)

5-Bromo-furan-2-carboxylic acid (1.68 g, 8.80 mmol) was coupled toaniline (80) (1.16 g, 8.80 mmol), using Method C. The residue waspurified by column chromatography eluting with 20% EtOAc in heptane togive the title compound.

Yield: 399 mg, 15%; LC/MS t_(r) 1.31 min; MS(ES+) m/z 305, 307 (M+H).

(ii) 5-Bromo-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (84)

Nitrile (83) (162 mg, 0.53 mmol) was treated with Me₃SnN₃ using MethodK. The residue was purified by column chromatography, flushing withheptane (200 ml) and eluting with 50% EtOAc in heptane to give the titlecompound.

Yield: 35 mg, 19%; LC/MS t_(r) 1.11 min; MS(ES+) m/z 348, 350 (M+H).

(iii) 5-(4-Fluoro-phenyl)-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (85)

The furyl bromide (84) (100 mg, 0.29 mmol) was coupled to4-fluoro-phenylboronic acid (44 mg, 0.32 mmol) using Method E. Thesolvents were removed in vacuo as described, but the residue wasdissolved in 2M NaOH (10 ml) and washed with EtOAc (2×10 ml). Theaqueous layer was acidified to pH 1 with 2M HCl until a whiteprecipitate formed and extracted with EtOAc (2×10 ml). The organic layerwas dried (MgSO₄), filtered and the solvent removed in vacuo to give thetitle compound. Yield: 13 mg, 12%; LC/MS t_(r) 1.32 min; MS(ES+) m/z 364(M+H); HPLC Purity: 87%; ¹H NMR (400 MHz, DMSO): δ 4.31 (s, 2H), 7.04(d, 1H), 7.17 (d, 1H), 7.32-7.41 (m, 4H), 7.61 (s, 1H), 7.73 (d, 1H),8.02 (t, 2H), 10.21 (s, 1H).

(h) 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (86) (i)5-(3-Fluoro-phenyl)-furan-2-carboxylic acid (3-cyanomethyl-phenyl)-amide

The furyl bromide (83) (135 mg, 0.44 mmol) was coupled to3-fluoro-phenylboronic acid (68 mg, 0.49 mmol) using Method E. The cruderesidue was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 40 mg, 28%; LC/MS t_(r) 1.47 min; MS(ES+) m/z 321 (M+H).

(ii) 5-(3-Fluoro-phenyl)-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (86)

The nitrile (40 mg, 0.13 mmol) was treated with TMSN₂ and Bu₂SnO usingMethod L. After a first treatment, TMSN₂ (58 mg, 0.50 mmol) and Bu₂SnO(6 mg, 0.025 mmol) were added, and the mixture was heated in themicrowave for a further 20 min. After work-up, the residue was dissolvedin MeOH (2 ml) and washed with heptane (3×3 ml). The layers wereseparated and the MeOH was removed in vacuo. The solid was thentriturated with heptane (4×2 ml) to give the title compound.

Yield: 16 mg, 34%; LC/MS t_(r) 1.42 min; MS(ES+) m/z 364 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO): δ 4.24 (s, 2H), 7.02 (d, 1H),7.18-7.34 (m, 3H), 7.37 (d, 1H), 7.52 (q, 1H), 7.59 (s, 1H), 7.69 (d,1H), 7.81 (d, 1H), 7.89 (d, 1H), 10.21 (s, 1H).

(i) 5-(4-Chloro-phenyl)-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (87)

The bromo-derivative (84) (100 mg, 0.29 mmol) was coupled to4-chloro-phenylboronic acid (49 mg, 0.32 mmol) using Method E. Afterreaction, the solvents were removed under a stream of N₂, and theresidue was dissolved in saturated NaHCO₂ solution (5 ml) and washedwith EtOAc (5 ml). The aqueous layer was acidified to pH 1 with 2M HCluntil a white precipitate formed and extracted with EtOAc (2×5 ml). Theorganic layer was dried (MgSO₄), filtered and the solvent removed invacuo. The residue was triturated with MeCN (4 ml) and further purifiedby preparative HPLC to give the title compound.

Yield: 11 mg, 10%; LC/MS t_(r) 1.52 min; MS(ES+) m/z 380, 382 (M+H);HPLC Purity: 100%; ¹H NMR (400 MHz, DMSO): δ 4.20 (s, 2H), 6.92 (d, 1H),7.12 (d, 1H), 7.20-7.29 (m, 2H), 7.42-7.50 (m, 3H), 7.60 (d, 1H), 7.89(d, 2H), 10.11 (s, 1H).

(j) 5-Phenyl-furan-2-carboxylic acid{3-[2-(1H-tetrazol-5-yl)-vinyl]-phenyl}-amide (89) (i)3-(3-Amino-phenyl)-acrylonitrile (88)

A solution of 3-(3-nitro-phenyl)-acrylonitrile (500 mg, 2.87 mmol) in 5%aqueous AcOH (10 ml) was heated to 80° C. Iron powder (1.44 g, 25.8mmol) was then added and the resulting mixture was stirred for 3 h. Thereaction mixture was filtered through celite and the filter cake washedwith MeCN (4×50 ml). The combined MeCN layers were evaporated in vacuoand the residue was re-dissolved in EtOAc (30 ml) and HCl (30 ml). Theaqueous layer was separated, basified to pH 10 with 6M NaOH, andextracted with EtOAc (3×80 ml). The combined organic layers were dried(MgSO₄), filtered and the solvent removed in vacuo to give the titlecompound.

Yield: 297 mg, 71%; LC/MS t_(r) 0.70 min; MS(ES+) m/z 186 (M+MeCN+H).

(ii) 5-Phenyl-furan-2-carboxylic acid [3-(2-cyano-vinyl)-phenyl]-amide

Carboxylic acid (56) (120 mg, 0.64 mmol) was coupled to aniline (88) (92mg, 0.64 mmol), using Method C to give the title compound.

Yield: 113 mg, 56%; LC/MS t_(r) 1.55 min; MS(ES+) m/z 315 (M+H).

(iii) 5-Phenyl-furan-2-carboxylic acid{3-[2-(1H-tetrazol-5-yl)-vinyl]-phenyl}-amide (89)

The nitrile (113 mg, 0.36 mmol) was treated with Me₃SnN₃ using Method K.After work-up, the residue was purified by column chromatography,flushing with heptane (200 ml) and eluting with 50% MeOH in EtOAc.Column chromatography was repeated eluting with 100% EtOAc. The solidwas further purified by preparative HPLC to give the title compound.Yield: 4.7 mg, 4%; LC/MS t_(r) 1.40 min; MS(ES+) m/z 358 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO): δ 7.22 (d, 1H), 7.33 (d, 1H),7.41-7.58 (m, 6H), 7.69 (d, 1H), 7.83 (d, 1H), 8.02 (d, 2H), 8.10 (s,1H), 10.32 (s, 1H).

(k) 5-(3-Chloro-phenyl)-furan-2-carboxylic acid{3-[2-(1H-tetrazol-5-yl)-vinyl]-phenyl}-amide (90) (i)5-Bromo-furan-2-carboxylic acid [3-(2-cyano-vinyl)-phenyl]-amide

5-Bromo-furan-2-carboxylic acid (716 mg, 3.75 mmol) was coupled toaniline (88) (540 mg, 3.75 mmol) using Method C. The residue waspurified by column chromatography eluting with 20% EtOAc in heptane, togive the title compound.

Yield: 451 mg, 38%; LC/MS t_(r) 1.39 min; MS(ES+) m/z 317, 319 (M+H).

(ii) 5-(3-Chloro-phenyl)-furan-2-carboxylic acid[3-(2-cyano-vinyl)-phenyl]-amide

The furyl bromide (150 mg, 0.47 mmol) was coupled to3-chloro-phenylboronic acid (81 mg, 0.52 mmol) using Method E. The cruderesidue was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 61 mg, 37%; LC/MS t_(r) 1.65 min; MS(ES+) m/z 349, 351 (M+H).

(iii) 5-(3-Chloro-phenyl)-furan-2-carboxylic acid{3-[2-(1H-tetrazol-5-yl)-vinyl]-phenyl}-amide (90)

The nitrile (61 mg, 0.18 mmol) was treated with TMSN₂ and Bu₂SnO usingMethod L. After work-up, the residue was dissolved in MeOH (2 ml) andwashed with heptane (3×3 ml). The layers were separated and the MeOH wasremoved in vacuo to give the title compound.

Yield: 18 mg, 26%; LC/MS t_(r) 1.48 min; MS(ES+) m/z 392, 394 (M+H);HPLC Purity: 98%; ¹H NMR (400 MHz, DMSO): δ 7.20-7.27 (m, 2H), 7.48-7.70(m, 5H), 7.67 (d, 1H), 7.77 (d, 1H), 7.90 (d, 1H), 8.05 (d, 2H), 10.34(s, 1H).

(l) 6-Phenyl-pyridine-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (92) (i)6-Bromo-pyridine-2-carboxylic acid (3-cyanomethyl-phenyl)-amide (91)

6-Bromo-pyridine-2-carboxylic acid (1.60 g, 12.1 mmol) was coupled toaniline (91) (2.44 g, 12.1 mmol) using Method C. The residue waspurified by column chromatography eluting with 20% EtOAc in heptane togive the title compound.

Yield: 1.20 g, 31%; LC/MS t_(r) 1.38 min; MS(ES+) m/z 316, 318 (M+H).

(ii) 6-Phenyl-pyridine-2-carboxylic acid (3-cyanomethyl-phenyl)-amide

The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled tophenylboronic acid (64 mg, 0.52 mmol) using Method E. The crude residuewas purified by column chromatography eluting with 20% EtOAc in heptaneto give the title compound.

Yield: 50 mg, 34%; LC/MS t_(r) 1.58 min; MS(ES+) m/z 314 (M+H).

(iii) 6-Phenyl-pyridine-2-carboxylic acid[3-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (92)

The nitrile (50 mg, 0.16 mmol) was treated with TMSN₃ and Bu₂SnO usingMethod L. After a first treatment, TMSN₃ (73 mg, 0.64 mmol) and Bu₂SnO(8 mg, 0.032 mmol) were added, and the mixture was heated in themicrowave for a further 20 min. After work-up, the residue was dissolvedin MeOH (2 ml) and washed with heptane (3×3 ml). The layers wereseparated and the MeOH was removed in vacuo. The solid was thentriturated with heptane (4×2 ml) to give the title compound.

Yield: 14 mg, 25%; LC/MS t_(r) 1.47 min; MS(ES+) m/z 357 (M+H); HPLCPurity: 98%; ¹H NMR (400 MHz, DMSO): δ 4.09 (s, 2H), 6.85 (d, 1H), 7.15(t, 1H), 7.27-7.39 (m, 3H), 7.58-7.63 (m, 2H), 7.86-7.96 (m, 2H), 8.03(d, 1H), 8.12 (d, 2H), 10.31 (s, 1H).

(m) 6-(4-Fluoro-phenyl)-pyridine-2-carboxylicacid[3-(1H-tetrazol-5ylmethyl)-phenyl]-amide (93) (i)6-(4-Fluoro-phenyl)-pyridine-2-carboxylic acid(3-cyanomethyl-phenyl)-amide

The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to4-fluoro-phenylboronic acid (73 mg, 0.52 mmol) using Method E. The cruderesidue was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 90 mg, 58%; LC/MS t_(r) 1.55 min; MS(ES+) m/z 332 (M+H).

(ii) 6-(4-Fluoro-phenyl)-pyridine-2-carboxylic acid[3-(1H-tetrazol-5ylmethyl)-phenyl]-amide (93)

The nitrile (90 mg, 0.27 mmol) was treated with TMSN₃ and Bu₂SnO usingMethod L. After a first treatment, further TMSN₃ (125 mg, 1.08 mmol) andBu₂SnO (14 mg, 0.054 mmol) were added and the mixture was heated in themicrowave for a further 20 min. After work-up, the residue was dissolvedin MeOH (2 ml) and washed with heptane (3×3 ml). The layers wereseparated and the MeOH was removed in vacuo. The solid was thentriturated with heptane (4×2 ml) to give the title compound.

Yield: 59 mg, 58%; LC/MS t_(r) 1.48 min; MS(ES+) m/z 375 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO): δ 4.25 (s, 2H), 7.02 (d, 1H),7.29-7.36 (m, 3H), 7.71-7.78 (m, 2H), 7.99-8.11 (m, 2H), 8.19 (d, 1H),8.34-8.40 (m, 2H), 10.49 (s, 1H).

(n) 6-(3-Fluoro-phenyl)-pyridine-2-carboxylic acid[3-(1H-tetrazol-5ylmethyl)-phenyl]-amide (94) (i)6-(3-Fluoro-phenyl)-pyridine-2-carboxylic acid(3-cyanomethyl-phenyl)-amide

The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to3-fluoro-phenylboronic acid (73 mg, 0.52 mmol) using Method E. The cruderesidue was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 144 mg, 93%; LC/MS t_(r) 1.56 min; MS(ES+) m/z 332 (M+H).

(ii) 6-(3-Fluoro-phenyl)-pyridine-2-carboxylic acid[3-(1H-tetrazol-5ylmethyl)-phenyl]-amide (93)

The nitrile (144 mg, 0.44 mmol) was treated with TMSN₂ and Bu₂SnO usingMethod L. After a first treatment, TMSN₃ (200 mg, 1.74 mmol) and Bu₂SnO(21 mg, 0.087 mmol) were added and the mixture was heated in themicrowave for a further 20 min. After work-up, the residue was dissolvedin MeOH (2 ml) and washed with heptane (3×3 ml). The layers wereseparated and the MeOH was removed in vacuo. The solid was thentriturated with heptane (4×2 ml) to give the title compound.

Yield: 92 mg, 56%; LC/MS t_(r) 1.58 min; MS(ES+) m/z 375 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO): δ 4.53 (s, 2H), 7.29 (d, 1H),7.51-7.62 (m, 2H), 7.75-7.83 (m, 1H), 7.99-8.05 (m, 2H), 8.29-8.40 (m,3H), 8.49-8.55 (m, 2H), 10.78 (s, 1H).

(o) 6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid[3-(1H-tetrazol-5ylmethyl)-phenyl]-amide (95) (i)6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid(3-cyanomethyl-phenyl)-amide

The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to4-chloro-phenylboronic acid (81 mg, 0.52 mmol) using Method E. The cruderesidue was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 113 mg, 691; LC/MS t_(r) 1.62 min; MS(ES+) m/z 348, 350 (M+H).

(ii) 6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid[3-(1H-tetrazol-5ylmethyl)-phenyl]-amide (95)

The nitrile (113 mg, 0.33 mmol) was treated with TMSN₃ and Bu₂SnO usingMethod L. After a first treatment, TMSN₃ (150 mg, 1.30 mmol) and Bu₂SnO(16 mg, 0.065 mmol) were added and the mixture was heated in themicrowave for a further 20 min. After work-up, the residue was dissolvedin MeOH (2 ml) and washed with heptane (3×3 ml). The layers wereseparated and the MeOH was removed in vacuo. The solid was thentriturated with heptane (4×2 ml) to give the title compound.

Yield: 78 mg, 60%; LC/MS t_(r) 1.53 min; MS(ES+) m/z 391, 393 (M+H);HPLC Purity: 97%; ¹H NMR (400 MHz, DMSO): δ 4.23 (s, 2H), 6.96 (d, 1H),7.27 (t, 1H), 7.50 (d, 2H), 7.68-7.74 (m, 2H), 7.99-8.08 (m, 2H), 8.15(d, 1H), 8.31 (d, 2H), 10.45 (s, 1H).

Example 9 (a)5-[(5-Phenyl-furan-2-carbonyl)-amino]-benzofuran-2-carboxylic acid (96)(i) 5-Nitro-benzofuran-2-carboxylic acid ethyl ester

5-Nitro-benzofuran-2-carboxylic acid (500 mg, 2.41 mmol) was esterifiedwith EtOH using Method A to give the title compound.

Yield: 488 mg, 86%; LC-MS t_(r) 1.44 min; MS(ES+) m/z (M+H) not present.

(ii) 5-Amino-benzofuran-2-carboxylic acid ethyl ester

5-Nitro-benzofuran-2-carboxylic acid ethyl ester (150 mg, 0.64 mmol) wasreduced using Method J to give the title compound.

Yield: 65 mg, 50%; LC-MS t_(r) 0.87 min; MS(ES+) m/z 206 (M+H).

(iii) 5-[(5-Phenyl-furan-2-carbonyl)-amino]-benzofuran-2-carboxylic acidethyl ester

Carboxylic acid (56) (60 mg, 0.32 mmol) was coupled to5-amino-benzofuran-2-carboxylic acid ethyl ester (65 mg, 0.32 mmol)using Method C to give the title compound.

Yield: 35 mg, 29%; LC-MS t_(r) 1.63 min; MS(ES+) m/z 376 (M+H).

(iv) 5-[(5-Phenyl-furan-2-carbonyl)-amino]-benzofuran-2-carboxylic acid(96)

The ester (35 mg, 0.093 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 25 mg, 77%; LC/MS t_(r) 1.38 min; MS(ES+) m/z 348 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, MeOD) δ 7.02 (d, 1H), 7.36-7.53 (m, 4H),7.61-7.64 (m, 2H), 7.75-7.80 (m, 1H) 7.95-7.99 (m, 2H), 8.20-8.21 (m,1H).

(b) 5-[(5-Phenyl-furan-2-carbonyl)-amino]-benzo[b]thiophene-2-carboxylicacid (97) (i) 5-Nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester

5-Nitro-benzofuran-2-carboxylic acid (500 mg, 2.24 mmol) was esterifiedwith EtOH using Method A to give the title compound.

Yield: 497 mg, 88%; LC-MS t_(r) 1.58 min; MS(ES+) m/z (M+H) not present.

(ii) 5-Amino-benzo[b]thiophene-2-carboxylic acid ethyl ester

5-Nitro-benzothiophene-2-carboxylic acid ethyl ester (160 mg, 0.64 mmol)was reduced using Method J to give the title compound.

Yield: 123 mg, 87%; LC-MS t_(r) 0.98 min; MS(ES+) m/z 222 (M+H).

(iii)5-[(5-Phenyl-furan-2-carbonyl)-amino]-benzo[b]thiophene-2-carboxylicacid ethyl ester

Carboxylic acid (56) (105 mg, 0.56 mmol) was coupled to5-amino-benzothiophene-2-carboxylic acid ethyl ester (123 mg, 0.56 mmol)using Method C to give the title compound.

Yield: 75 mg, 34%; LC-MS t_(r) 1.72 min; MS(ES+) m/z 392 (M+H).

(iv)5-[(5-Phenyl-furan-2-carbonyl)-amino]-benzo[b]thiophene-2-carboxylicacid (97)

The ester (75 mg, 0.19 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 43 mg, 62%; LC/MS t_(r) 1.47 min; MS(ES+) m/z 363 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, MeOD) δ 7.03 (d, 1H), 7.39-7.42 (m, 2H),7.48-7.52 (m, 2H), 7.82-7.85 (m, 1H), 7.94-7.99 (m, 3H) 8.07-8.10 (m,1H), 8.42-8.43 (m, 1H).

(c) 2-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-benzylidene}-butyric acid(98) (i) 2-(3-Nitro-benzylidene)-butyric acid ethyl ester

2-(3-Nitro-benzylidene)-butyric acid (500 mg, 2.27 mmol) was esterifiedby dissolving in EtOH (12.5 ml), adding conc HCl (0.25 ml) and heatingto reflux for 8 h. The solvents were evaporated in vacuo to give thetitle compound.

Yield: 440 mg, 78%; LC-MS t_(r) 1.64 min; MS(ES+) m/z (M+H) not present.

(ii) 2-(3-Amino-benzylidene)-butyric acid ethyl ester

2-(3-Nitro-benzylidene)-butyric acid ethyl ester (230 mg, 0.92 mmol) wasreduced using Method J to give the title compound.

Yield: 186 mg, 92%; LC-MS t_(r) 1.06 min; MS(ES+) m/z 220 (M+H).

(iii) 2-{3-[(5-Bromo-furan-2-carbonyl)-amino]-benzylidene}-butyric acidethyl ester

5-Bromo-furan-2-carboxylic acid (88 mg, 0.46 mmol) was coupled to2-(3-amino-benzylidene)-butyric acid ethyl ester (100 mg, 0.46 mmol)using Method C to give the title compound.

Yield: 132 mg, 73%; LC-MS t_(r) 1.66 min; MS(ES+) m/z 392, 394 (M+H).

(iv) 2-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-benzylidene}-butyric acidethyl ester

The furyl bromide (132 mg, 0.34 mmol) was coupled to phenylboronic acid(45 mg, 0.37 mmol) using Method E. The residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 36 mg, 27%; LC-MS t_(r) 1.78 min; MS(ES+) m/z 390 (M+H).

(v) 2-{3-[(5-Phenyl-furan-2-carbonyl)-amino]-benzylidene}-butyric acid(98)

The ester (35 mg, 0.090 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 7.6 mg, 23%; LC/MS t_(r) 1.49 min; MS(ES+) m/z 362 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, MeOD) δ 1.23 (t, 3H), 3.33 (q, 2H) 7.01(d, 1H), 7.20-7.23 (m, 1H), 7.39-7.52 (m, 5H), 7.67-7.70 (m, 2H)7.95-7.98 (m, 3H).

(d) 3-(3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (100) (i) 3-{3-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-acrylicacid ethyl ester (99)

5-Bromo-furan-2-carboxylic acid (150 mg, 0.78 mmol) was coupled toaniline (60) (150 mg, 0.78 mmol) using Method C to give the titlecompound.

Yield: 125 mg, 44%; LC-MS t_(r)1.53 min; MS(ES+) m/z 364, 366 (M+H).

(ii) 3-(3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

The furyl bromide (99) (125 mg, 0.34 mmol) was coupled to3-fluoro-phenylboronic acid (48 mg, ×0.41 mmol) acid using Method E. Theresidue was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 96 mg, 74%; LC-MS t_(r) 1.68 min; MS(ES+) m/z 380 (M+H)

(iii)3-(3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic acid(100)

The ester (96 mg, 0.25 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 58 mg, 66%; LC/MS t_(r) 1.42 min; MS(ES+) m/z 352 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, DMSO) δ 6.51 (d, 1H), 7.22-7.63 (m, 7H),7.83-8.01 (m, 4H), 10.31 (s, 1H), 12.43 (s, 1H).

(e)3-{3-[(5-Benzo[1,3]dioxol-5-yl-furan-2-carbonyl)-amino]-phenyl}-acrylicacid (101)

The furyl bromide (99) (100 mg, 0.30 mmol) was coupled to3,4-(methylenedioxy)-phenylboronic acid (54 mg, 0.33 mmol) using MethodE. During this reaction, hydrolysis occurred. The crude reaction mixturewas diluted with H₂O (4 ml) and extracted with EtOAc (3×1 ml), then theaqueous layer was acidified with 2M HCl until a white precipitateappeared and extracted with DCM (3×1 ml). The organic layer was dried(MgSO₄), filtered and the solvent removed in vacuo. The solid wastriturated with TBME (2×2 ml) to give the title compound.

Yield: 27 mg, 24%; LC/MS t_(r) 1.99 min; MS(ES+) m/z 378 (M+H); HPLCPurity: 93%; ¹H NMR (250 MHz; DMSO): δ 6.10 (s, 2H), 6.50 (d, 1H),7.02-7.05 (m, 2H), 7.33-7.68 (m, 6H), 7.78-7.88 (m, 1H), 8.00 (s, 1H),10.21 (s, 1H).

(f)3-(3-{[5-(3,5-Bis-trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}phenyl)-acrylicacid (102) (i)3-(3-{[5-(3,5-Bis-trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}phenyl)-acrylicacid ethyl ester

The furyl bromide (99) (70 mg, 0.19 mmol) was coupled to3,5-bis-trifluoromethyl-phenylboronic acid (55 mg, 0.21 mmol) acid usingMethod E, except that the reaction was heated at 100° C. The crudeproduct was purified by column chromatography eluting with a steppedgradient of 0-10% EtOAc in heptane to give the title compound.

Yield: 45 mg, 47%; LC-MS t_(r) 1.87 min; MS(ES+) m/z 498 (M+H).

(ii)3-(3-{[5-(3,5-Bis-trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}phenyl)-acrylicacid (102)

To a solution of the ester (45 mg, 0.09 mmol) in THF (1 ml) and MeOH (1ml) was added 1M NaOH (2 ml) and the resulting solution was stirred for1 h at 4.0° C. The THF and MeOH were removed in vacuo then 2M HCl wasadded until a white precipitate formed. The aqueous layer was extractedwith DCM (3×1 ml). The organic layer was dried (MgSO₄), filtered and thesolvent was removed in vacuo. The solid was triturated with 50% DCM inheptane (2×2 ml) and 50% MeOH in H₂O (2×2 ml) to give the titlecompound.

Yield: 15 mg, 36%; LC/MS t_(r) 2.23 min; MS(ES+) m/z 470 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD): δ 6.52 (d, 1H), 7.25-7.28 (m, 1H),7.30-7.37 (m, 3H), 7.59 (d, 1H), 7.69-7.73 (m, 1H), 7.38 (d, 2H), 8.50(s, 2H).

(g) 3-{3-[(5-Biphenyl-3-yl-furan-2-carbonyl)-amino]-phenyl}-acrylic acid(103) (i)3-{3-[(5-Biphenyl-3-yl-furan-2-carbonyl)-amino]-phenyl}-acrylic acidethyl ester

Bromo-derivative (99) (70 mg, 0.19 mmol) was coupled tobiphenyl-3-boronic acid (42 mg, 0.21 mmol) acid using Method E, exceptthat the reaction was heated at 100° C. The crude product was purifiedby column chromatography eluting with a stepped gradient of 0-10% EtOAcin heptane to give the title compound.

Yield: 33 mg, 39%; LC-MS t_(r) 1.86 min; MS(ES+) m/z 438 (M+H).

(ii) 3-{3-[(5-Biphenyl-3-yl-furan-2-carbonyl)-amino]-phenyl}-acrylicacid (103)

To a solution of the ester (33 mg, 0.075 mmol) in THF (2 ml) and MeOH (2ml) was added 1M NaOH (4 ml) and the resulting solution was stirred for1 h at 40° C. The THF and MeOH were removed in vacuo and the aqueouslayer was extracted with TBME (2×2 ml). The aqueous layer was acidifiedwith 6M HCl until a white precipitate formed. This was then extractedwith TBME (3×2 ml). The organic layer was dried (MgSO₄), filtered andthe solvent was removed in vacuo. The residue was suspended in H₂O (1ml), MeOH (1 ml) and heptane (1 ml) and the resulting solid was filteredand dried in vacuo to give the title compound.

Yield: 15 mg, 46%; LC/MS t_(r) 2.21 min; MS(ES+) m/z 410 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz; MeOD): δ 6.72 (d, 1H), 7.29 (d, 1H),7.56-7.72 (m, 6H), 7.73-7.79 (t, 1H), 7.83-7.97 (m, 4H), 8.01 (d, 1H),8.12 (d, 1H), 8.19 (s, 1H), 8.43 (s, 1H).

(h)3-(3-{[5-(3-Benzyloxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (104) (i)3-(3-{[5-(3-Benzyloxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

The furyl bromide (99) (100 mg, 0.28 mmol) was coupled to3-benzyloxy-phenylboronic acid (69 mg, 0.30 mmol) acid using Method E,except that the reaction was heated at 85° C. The crude product waspurified by column chromatography eluting with 20% EtOAc in heptane togive the title compound.

Yield: 86 mg, 67%; LC-MS t_(r) 1.83 min; MS(ES+) m/z 468 (M+H).

(ii)3-(3-{[5-(3-Benzyloxy-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (104)

The ester (86 mg, 0.18 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 36 mg, 45%; LC/MS t_(r) 1.65 min; MS(ES+) m/z 440 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, DMSO) δ 5.19 (s, 2H), 6.51 (d, 1H),6.67-7.05 (m, 2H), 7.28-7.45 (m, 7H), 7.46-7.54 (m, 3H), 7.62-7.73 (m,2H), 7.80-7.88 (m, 1H), 8.01 (s, 1H).

(i)3-(3-{[5-(2-Fluoro-biphenyl-4-yl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (105) (i)3-(3-{[5-(2-Fluoro-biphenyl-4-yl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

The furyl bromide (99) (100 mg, 0.28 mmol) was coupled to2-Fluoro-biphenyl-4-boronic acid (65 mg, 0.30 mmol) acid using Method E,except that the reaction was heated at 85° C. The crude product waspurified by column chromatography eluting with 20% EtOAc in heptane togive the title compound.

Yield: 67 mg, 54%; LC-MS t_(r) 1.89 min; MS(ES+) m/z 456 (M+H).

(ii)3-(3-{[5-(2-Fluoro-biphenyl-4-yl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (105)

The ester (67 mg, 0.15 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 43 mg, 67%; LC/MS t_(r) 2.23 min; MS(ES+) m/z 440 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, DMSO) δ 6.53 (d, 1H), 7.38 (d, 1H),7.42-7.59 (m, 6H), 7.60-7.73 (m, 4H), 7.87 (d, 1H), 7.94 (d, 1H),8.01-8.09 (m, 2H), 10.35 (s, 1H), 12.52 (broad s, 1H).

(j) 3-{3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylic acid(107) (i) 3-[3-(5-Bromo-2-fluoro-benzoylamino)-phenyl]-acrylic acidethyl ester (106)

5-Bromo-2-fluorobenzoic acid (330 mg, 1.5 mmol) was coupled to aniline(99) (290 mg, 1.5 mmol) using Method C to give the title compound.

Yield: 525 mg, 89%; LC-MS t_(r)1.61 min; MS(ES+) m/z 392, 394 (M+H).

(ii) 3-{3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylic acidethyl ester

The phenyl bromide (106) (100 mg, 0.25 mmol) was coupled tophenylboronic acid (34 mg, ×0.28 mmol) using Method E. The residue waspurified by column chromatography eluting with 20% EtOAc in heptane togive the title compound.

Yield: 38 mg, 39%; LC-MS t_(r) 1.72 min; MS(ES+) m/z 390 (M+H).

(iii) 3-{3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylic acid(107)

The ester (38 mg, 0.098 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 29 mg, 82%; LC/MS t_(r) 1.46 min; MS(ES+) m/z 362 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, MeOD) δ 6.54 (d, 1H), 7.34-7.53 (m, 6H),7.66-7.88 (m, 5H), 7.99-8.03 (m, 2H).

(k) 3-{3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid (108) (i)3-{3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylic acidethyl ester

The phenyl bromide (106) (100 mg, 0.25 mmol) was coupled to3-fluoro-phenylboronic acid (39 mg, 0.28 mmol) using Method E. The crudeproduct was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 17 mg, 17%; LC-MS t_(r) 1.73 min; MS(ES+) m/z 408 (M+H).

(ii) 3-{3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid (108)

The ester (17 mg, 0.042 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 13 mg, 82%; LC/MS t_(r) 1.46 min; MS(ES+) m/z 380 (M+H). HPLCPurity: 100%; ¹H NMR (250 MHz, MeOD) δ 6.54 (d, 1H), 7.08-7.20 (m, 1H),7.35-7.53 (m, 6H), 7.69 (d, 1H), 7.78-7.90 (m, 2H), 7.99-8.04 (m, 2H).

(l)3-(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (110) (i)3-{3-[(6-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-acrylic acid ethylester (109)

6-Bromo-pyridine-2-carboxylic acid (127 mg, 0.63 mmol) was coupled toaniline (60) (120 mg, 0.63 mmol) using Method C to give the titlecompound.

Yield: 201 mg, 85%; LC-MS t_(r)1.62 min; MS(ES+) m/z 375, 377 (M+H).

(ii)3-(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

The pyridyl bromide (109) (100 mg, 0.27 mmol) was coupled to3-fluoro-phenylboronic acid (41 mg, 0.29 mmol) using Method E. Theresidue was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 36 mg, 34%; LC-MS t_(r) 1.79 min; MS(ES+) m/z 391 (M+H).

(iii)3-(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (110)

The ester (36 mg, 0.092 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 23 mg, 69%; LC/MS t_(r) 1.53 min; MS(ES+) m/z 363 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, MeOD) δ 6.54-6.64 (m, 1H), 7.22-7.30 (m,1H), 7.43-7.60 (m, 3H), 7.70-7.76 (m, 1H), 7.89-7.93 (m, 1H), 8.05-8.13(m, 6H).

(m) 3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid(111) (i) {3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-aceticacid ethyl ester

The phenyl bromide (78) (106 mg, 0.28 mmol) was coupled to3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. The crudeproduct was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 66 mg, 60%; LC-MS t_(r) 1.63 min; MS(ES+) m/z 396 (M+H).

(ii) 3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acetic acid(111)

The ester (66 mg, 0.17 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 52 mg, 85%; LC/MS t_(r) 1.58 min; MS(ES+) m/z 368 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, MeOD) δ 3.65 (s, 2H), 7.07-7.19 (m, 2H),7.32-7.51 (m, 5H), 7.65-7.68 (m, 2H), 7.80-7.86 (m, 1H), 7.96-8.00 (m,1H).

(n) 3-{3-[(4,4′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid (112) (i) 4,4′-Difluoro-biphenyl-3-carboxylic acid

5-Bromo-2-fluorobenzoic acid (250 mg, 1.14 mmol) was coupled to4-fluoro-phenylboronic acid (192 mg, 1.37 mmol) using Method E to givethe title compound. No chromatography was necessary.

Yield: 209 mg, 78%; LC-MS t_(r)1.36 min; MS(ES+) m/z (M+H) not present.

(ii) 3-{3-[(4,4′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid ethyl ester

4,4′-Difluoro-biphenyl-3-carboxylic acid (100 mg, 0.43 mmol) was coupledto aniline (60) (82 mg, 0.43 mmol) using Method C to give the titlecompound.

Yield: 119 mg, 68%; LC-MS t_(r) 1.73 min; MS(ES+) m/z 408 (M+H).

(iii) 3-{3-[(4,4′-Difluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid (112)

The ester (119 mg, 0.29 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 85 mg, 77%; LC/MS t_(r) 1.56 min; MS(ES+) m/z 380 (M+H); HPLCPurity: 98%; ¹H NMR (250 MHz, MeOD) δ 6.53 (d, 1H), 7.19-7.27 (m, 2H),7.33-7.49 (m, 3H), 7.67-7.86 (m, 5H), 7.96-8.00 (m, 2H).

(o) (3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-aceticacid (113) (i)(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acetic acidethyl ester

The pyridyl bromide (77) (100 mg, 0.28 mmol) was coupled to3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. The crudeproduct was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 95 mg, 90%; LC-MS t_(r) 1.69 min; MS(ES+) m/z 379 (M+H).

(ii) (3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-aceticacid (113)

The ester (95 mg, 0.25 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 57 mg, 65%; LC/MS t_(r) 1.54 min; MS(ES+) m/z 351 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, MeOD) δ 3.68 (s, 2H), 7.13-7.28 (m, 2H),7.35-7.41 (m, 1H), 7.52-7.61 (m, 1H), 7.76-7.79 (m, 2H), 8.01-8.21 (m,5H).

(p) 3-{3-[(2-Phenyl-thiazole-4-carbonyl)-amino]-phenyl}-acrylic acid(115) (i) 3-{3-[(2-Chloro-thiazole-4-carbonyl)-amino]-phenyl}-acrylicacid ethyl ester (114)

Carboxylic acid (79) (220 mg, 1.34 mmol) was coupled to aniline (60)(257 mg, 1.34 mmol) using Method C to give the title compound.

Yield: 260 mg, 57%; LC/MS t_(r) 1.54 min; MS(ES+) m/z 337 (M+H).

(ii) 3-{3-[(2-Phenyl-thiazole-4-carbonyl)-amino]-phenyl}-acrylic acidethyl ester

The chloro thiazole (114) (80 mg, 0.24 mmol) was coupled tophenylboronic acid (32 mg, 0.26 mmol) using Method E, except that thereaction mixture was heated for a total of 4 h. The crude residue waspurified by column chromatography eluting with 25% EtOAc in heptane togive the title compound.

Yield: 52 mg, 57%; LC/MS t_(r) 1.76 min; MS(ES+) m/z 379 (M+H).

(iii) 3-{3-[(2-Phenyl-thiazole-4-carbonyl)-amino]-phenyl}-acrylic acid(115)

The ester (52 mg, 0.14 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 31 mg, 63%; LC/MS t_(r) 2.06 min; MS(ES+) m/z 351 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, DMSO) δ 6.53 (d, 1H), 7.44-7.47 (m, 2H),7.55-7.61 (m, 4H), 7.96-8.01 (m, 1H), 8.13-8.21 (m, 3H), 8.53 (s, 1H),10.33 (s, 1H).

(q)3-(3-{[2-(3-Fluoro-phenyl)-thiazole-4-carbonyl]-amino}-phenyl)-acrylicacid (116) (i)3-(3-{[2-(3-Fluoro-phenyl)-thiazole-4-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

The chloro thiazole (114) (80 mg, 0.24 mmol) was coupled to3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E, exceptthat the reaction mixture was heated for a total of 12 h. The cruderesidue was purified by column chromatography eluting with 20% EtOAc inheptane to give the title compound.

Yield: 35 mg, 37%; LC/MS t_(r) 1.76 min; MS(ES+) m/z 397 (M+H).

(ii)3-(3-{[2-(3-Fluoro-phenyl)-thiazole-4-carbonyl]-amino}-phenyl)-acrylicacid (116)

The ester (35 mg, 0.088 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 6.3 mg, 19%; LC/MS t_(r) 1.45 min; MS(ES+) m/z 369 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz, d⁶-Acetone) δ 6.57 (d, 1H), 7.52-7.40 (m,1H), 7.49 (d, 2H), 7.56-7.74 (m, 2H), 7.93-8.06 (m, 3H), 8.22 (s, 1H),8.48 (s, 1H), 10.14 (s, 1H).

(r) [3-(Biphenyl-3-ylcarbamoyl)-phenyl]-acetic acid (117) (i)Biphenyl-3-ylamine

Bromobenzene (300 mg, 1.91 mmol) was coupled to 3-amino-phenylboronicacid (355 mg, 2.29 mmol) using Method E. The crude residue wasre-dissolved in EtOAc (8 ml) and washed with saturated NaHCO₃ (3×8 ml).The organic layer was extracted with 1.2M HCl (1×8 ml) then basifiedwith 6M NaOH until a white precipitate formed. This was then extractedwith EtOAc (3×10 ml). The combined organic layers were dried (MgSO₄),filtered and the solvent removed in vacuo to give the title compound.Yield: 297 mg, 92%; LC/MS t_(r) 0.96 min; MS(ES+) m/z 170 (M+H).

(ii) 3-Cyanomethyl-benzonitrile

3-Bromomethyl-benzonitrile (150 mg, 0.76 mmol) was dissolved in DMF (2ml). KCN (55 mg, 0.84 mmol) was dissolved in the minimum amount of waterand was added to the reaction. The resulting solution was stirred at 85°C. overnight. The reaction mixture was allowed to cool to roodtemperature, EtOAc (5 ml) was added, and the solution was washed withsaturated NaHCO₃ (4×10 ml). The organic layer was dried (MgSO₄),filtered and the solvent removed in vacuo to give the title compound.Yield: 90 mg, 83%; LC/MS t_(r) 1.04 min; MS(ES+) m/z 143 (M+H).

(iii) 3-Carboxymethyl-benzoic acid

3-Cyanomethyl-benzonitrile (90 mg, 0.63 mmol) was suspended in conc. HCl(3 ml), and heated to 80° C. for 2 h. The solvent was then removed invacuo to give the crude product, which was used without furtherpurification.

Yield: 110 mg, 97%; LC/MS t_(r) 0.71 min; MS(ES+) m/z 181 (M+H).

(iv) 3-Ethoxycarbonylmethyl-benzoic acid

The phenylacetic acid (110 mg, 0.61 mmol) was esterified with EtOH usingMethod A to give the crude product, which was used without furtherpurification.

Yield: 126 mg, 99%; LC/MS t_(r) 1.13 min; MS(ES+) m/z 209 (M+H).

(v) [3-(Biphenyl-3-ylcarbamoyl)-phenyl]-acetic acid ethyl ester

3-Ethoxycarbonylmethyl-benzoic acid (126 mg, 0.61 mmol) was coupled tobiphenyl-3-ylamine (105 mg, 0.62 mmol) using Method C. The residue waspurified by column chromatography eluting with 100% DCM to give thetitle compound.

Yield: 17 mg, 8%; LC/MS t_(r) 1.64 min; MS(ES+) m/z 360 (M+H).

(vi) [3-(Biphenyl-3-ylcarbamoyl)-phenyl]-acetic acid (117)

The ester (17 mg, 0.047 mmol) was hydrolysed with NaOH (34 mg, 0.85 mmolusing Method G to give the title compound.

Yield: 7.8 mg, 50%; LC/MS t_(r) 1.46 min; MS(ES+) m/z 332 (M+H); HPLCPurity: 96%; ¹H NMR (400 MHz; CDCl₃): δ 3.78 (s, 2H), 7.37-7.42 (m, 1H),7.44-7.59 (m, 6H), 7.66-7.76 (m, 3H), 7.88-7.94 (m, 2H), 8.04 (s, 1H).

(s)1-Methyl-5-[(5-phenyl-furan-2-carbonyl)-amino]-1H-indole-2-carboxylicacid (118) (i) 1-Methyl-5-nitro-1H-indole-2-carboxylic acid

5-Nitro-1H-indole-2-carboxylic acid ethyl ester (234 mg, 1 mmol) wasdissolved in DMF (2 ml). NaH (32 mg, 1.4 mmol) was added as a suspensionin heptane (0.5 ml) and the mixture was stirred at room temperature for10 min. Iodomethane (170 mg, 1.2 mmol) was added drop-wise and thesolution was left stirring for 1 h. During this reaction, hydrolysisoccurred. The reaction mixture was quenched with H₂O (2 ml) and washedwith EtOAc (3×1 ml). The aqueous layer was acidified to pH 1 with conc.HCl until a white precipitate formed and extracted with EtOAc (3×1 ml).These organic layer were combined, dried (MgSO₄), filtered and thesolvent removed in vacuo to give the title compound. Yield: 99 mg, 45%;LC/MS t_(r) 1.24 min; MS(ES+) m/z (M+H) not present; ¹H NMR (400 MHz;DMSO) δ 4.10 (s, 3H), 7.52 (s, 1H), 7.81 (d, 1H), 8.16-8.20 (m, 1H),8.74 (d, 1H).

(ii) 1-Methyl-5-nitro-1H-indole-2-carboxylic acid methyl ester

1-Methyl-5-nitro-1H-indole-2-carboxylic acid (99 mg, 0.45 mmol) wasesterified with MeOH using Method A to give the title compound.

Yield: 70 mg, 66%; LC/MS t_(r) 1.45 min; MS(ES+) m/z 235 (M+H).

(iii) 5-Amino-1-methyl-1H-indole-2-carboxylic acid methyl ester

1-Methyl-5-nitro-1H-indole-2-carboxylic acid methyl ester (70 mg, 0.3mmol) was dissolved in DMF (5 ml) and SnCl₂.2H₂O (339 mg, 1.5 mmol) wasadded as a solid. The resulting solution was stirred at 60° C. for 4 h.After cooling to room temperature, a pre-mixed aqueous solution ofsaturated Rochelle's salt (3 ml) and saturated NaHCO₃ (3 ml) was addedto the reaction mixture and the aqueous layer was extracted with EtOAc(3×6 ml). The organic layer was washed with H₂O (3 ml), 1:1 NaHCO₃:Rochelle's salt solution (3 ml), dried (MgSO₄), filtered and the solventwas removed in vacuo to give the title compound.

Yield: 25 mg, 41%; LC-MS t_(r) 0.85 min; MS(ES+) m/z 205 (M+H).

(iv)1-Methyl-5-[(5-phenyl-furan-2-carbonyl)-amino]-1H-indole-2-carboxylicacid methyl ester

Carboxylic acid (56) (23 mg, 0.12 mmol) was coupled to5-amino-1-methyl-1H-indole-2-carboxylic acid methyl ester (25 mg, 0.12mmol) using Method D to give the title compound.

Yield: 31 mg, 69%; LC-MS t_(r) 1.59 min; MS(ES+) m/z 375 (M+H).

(v)1-Methyl-5-[(5-phenyl-furan-2-carbonyl)-amino]-1H-indole-2-carboxylicacid (118)

The ester (31 mg, 0.08 mmol) was dissolved in MeOH (2 ml) and 1M NaOH (1ml). The suspension was stirred at room temperature for 1 h, upon whichTHF (2 ml) was added. 1M NaOH (1 ml) was added after 1 h. The resultingsolution was stirred for 30 min at room temperature, then THF and MeOHwere removed in vacuo. The basic solution was extracted with EtOAc (2×1ml) and DCM (2×1 ml). The organic layers were dried (MgSO₄), filtered,combined, and evaporated in vacuo to give the title compound.

Yield: 19 mg, 66%; LC/MS t_(r) 1.50 min; MS(ES+) m/z 361 (M+H); HPLCPurity: 95%; ¹H NMR (400 MHz; MeOD) δ 4.00 (s, 3H), 6.89 (s, 1H),6.92-7.02 (m, 1H), 7.25 (d, 1H), 7.22-7.46 (m, 4H), 7.42 (d, 1H),7.80-7.88 (m, 3H).

Example 10 (a)3-{3-[2-Oxo-2-(5-phenyl-furan-2-yl)-ethyl]-phenyl}-acrylic acid (120)(i) 2-Phenyl-furan (119)

Bromobenzene (1.5 g, 9.55 mmol) was coupled to 2-furylboronic acid (1.75g, 15.6 mmol) using Method E. The crude compound was purified by columnchromatography using a stepped gradient of 5-10% EtOAc in heptane togive the title compound.

Yield: 1.23 g, 89%; LC/MS t_(r) 1.55 min; MS(ES+) m/z (M+H) not present;¹H NMR (400 MHz; DMSO) δ 6.46-6.48 (m, 1H), 6.65 (d, 1H), 7.25 (t, 1H),7.38 (t, 2H), 7.46-7.47 (m, 1H), 7.67 (d, 2H).

(ii) 2-(3-Bromo-phenyl)-1-(5-phenyl-furan-2-yl)-ethanone

2-Phenyl-furan (119) (50 mg, 0.28 mmol) and (3-bromo-phenyl)-acetic acid(134 mg, 0.63 mmol) were dissolved in ortho-dichlorobenzene (4 ml). P₂O₅(202 mg, 1.42 mmol) was added as a suspension in ortho-dichlorobenzene(2 ml). The reaction mixture was heated to 80° C. for 2 h and cooled toroom temperature overnight. After the addition of further P₂O₅ (202 mg,1.42 mmol), heating was resumed at 90° C. for 3 h. The reaction mixturewas cooled to 0° C. and quenched with H₂O (15 ml). The organic layer wasseparated and the aqueous layer was washed with DCM (3×10 ml). Thecombined organic layers were dried (MgSO₄), filtered and the DCM removedin vacuo. The ortho-dichlorobenzene solution was loaded to a silica-gelcolumn and flushed with heptane (100 ml). The title compound was theneluted with 10% EtOAc in heptane.

Yield: 60 mg, 63%; LC/MS t_(r) 1.72 min; MS(ES+) m/z 341, 343 (M+H).

(iii) 3-{3-[2-Oxo-2-(5-phenyl-furan-2-yl)-ethyl]-phenyl}-acrylic acidmethyl ester

Acrylic acid methyl ester (15 mg, 0.18 mmol) and Et₃N (59 mg, 0.59 mmol)were added to a microwave tube. Palladium (II) acetate (1.6 mg, 0.05mmol) in MeCN solution (0.5 ml), tri-o-tolyl-phosphine (4.5 mg, 0.015mmol) in MeCN solution (0.5 ml), and the phenyl bromide (50 mg, 0.15mmol) in MeCN solution (3 ml) were then added. The solution was heatedin a CEM Discover microwave for 2×15 min at 90° C. (150 W, 250 psi). Thesolvent was removed in vacuo and the residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 22 mg, 42%; LC/MS t_(r) 1.61 min; MS(ES+) m/z 347 (M+H).

(iv) 3-{3-[2-Oxo-2-(5-phenyl-furan-2-yl)-ethyl]-phenyl}-acrylic acid(120)

The ester (22 mg, 0.063 mmol) was dissolved in MeOH (1 ml), THF (0.2 ml)and 1M NaOH (1 ml). The suspension was stirred at room temperature for 1h. The solution was extracted with EtOAc (2×1 ml). Further 1M NaOH wasadded (1 ml) and extraction was repeated with EtOAc (2×1 ml). Theaqueous layer was acidified to pH 1 with conc. HCl and extracted withEtOAc (2×1 ml). The organic layer was filtered through MgSO₄ and thesolvent removed in vacuo. The solid was triturated with DCM (0.5 ml) togive the title compound.

Yield: 1.3 mg, 6%; LC/MS t_(r) 1.44 min; MS(ES+) m/z 333 (M+H); HPLCPurity: 97%; ¹H NMR (250 MHz; MeOD) δ 4.29 (s, 2H), 6.53 (d, 1H), 7.05(d, 1H), 7.38-7.53 (m, 6H), 7.59 (d, 1H), 7.62-7.74 (m, 2H), 7.85-7.92(m, 2H).

(b) 3-[3-(2-Phenyl-thiazol-4-ylmethoxy)-phenyl]-acrylic acid (121) (i)3-(3-Hydroxy-phenyl)-acrylic acid methyl ester

3-(3-Hydroxy-phenyl)-acrylic acid (2 g, 12.2 mmol) was esterified withMeOH using Method B to give the title compound.

Yield: 2.09 g, 96%; LC/MS t_(r) 1.13 min; MS(ES+) m/z 179 (M+H).

(ii) 3-[3-(2-Phenyl-thiazol-4-ylmethoxy)-phenyl]-acrylic acid methylester

3-(3-Hydroxy-phenyl)-acrylic acid methyl ester (85 mg, 0.48 mmol) wasdissolved in dry DMF (1.5 ml) and NaH (14 mg, 0.60 mmol) was added as asuspension in heptane (0.5 ml). The mixture was stirred at roomtemperature for 10 min. 4-Chloromethyl-2-phenyl-thiazole (100 mg, 0.48mmol) was added portion-wise and the solution left stirring for 4 h. Thereaction mixture was quenched with H₂O (2 ml) and extracted with EtOAc(3×1 ml). The combined organic layers were washed with H₂O (3×1 ml),dried (MgSO₄), filtered and the solvent removed in vacuo to give amixture of acid and ester, which was used without further purification.

For the ester: LC/MS t_(r) 1.64 min; MS(ES+) m/z 352 (M+H).

(iii) 3-[3-(2-Phenyl-thiazol-4-ylmethoxy)-phenyl]-acrylic acid (122)

The mixture (167 mg, 0.47 mmol) was stirred in MeOH (3 ml), 4M NaOH (3ml) and THF (3 ml) for 30 min. The solution was extracted with EtOAc(3×5 ml) and the aqueous layer was acidified with conc. HCl until awhite precipitate formed. This was extracted with EtOAc (3×5 ml). Thecombined organic layers were dried (MgSO₄), filtered and the solventremoved in vacuo to give the title compound.

Yield: 156 mg, 98% over 2 steps; LC/MS t_(r) 1.58 min; MS(ES+) m/z 338(M+H); HPLC Purity: 100%; ¹H NMR (250 MHz; DMSO): δ 5.23 (s, 2H), 6.5(broad d, 1H), 7.02 (broad d, 1H), 7.09-7.18 (m, 2H), 7.22-7.35 (m, 2H),7.42-7.58 (m, 3H), 7.78 (s, 1H), 7.89-7.99 (m, 2H).

(c) 3-[3-(2-Phenyl-thiazol-4-ylmethylsulfanyl)-phenyl]-acrylic acid(122) (i) 4-(3-Bromo-phenylsulfanylmethyl)-2-phenyl-thiazole

NaH (53 mg, 2.2 mmol) was suspended in dry THF (1.5 ml) under a streamof N₂ and 3-bromo-benzenethiol (378 mg, 2 mmol) was added dropwise tothe suspension over 5 min. 4-Chloromethyl-2-phenyl-thiazole (419 mg, 2mmol) was added and the solution left stirring overnight. The reactionmixture was quenched with a saturated K₂CO₃ solution (8 ml) andextracted with EtOAc (3×4 ml). The combined organic layers were washedwith saturated K₂CO₃ solution (4 ml), dried (MgSO₄), filtered and thesolvent removed in vacuo. The residue was purified by columnchromatography eluting with 20% EtOAc in heptane to give the titlecompound.

Yield: 630 mg, 87%; LC/MS t_(r) 1.85 min; MS(ES+) m/z 362, 364 (M+H).

(ii) 3-[3-(2-Phenyl-thiazol-4-ylmethylsulfanyl)-phenyl]-acrylic acidmethyl ester

Acrylic acid methyl ester (28 mg, 0.33 mmol) and Et₃N (113 mg, 1.12mmol) were added to a microwave tube. Palladium (II) acetate (3 mg,0.014 mmol) in MeCN solution (0.5 ml), tri-o-tolyl-phosphine (4.5 mg,0.028 mmol) in MeCN solution (0.5 ml), and the bromo-derivative (100 mg,0.28 mmol) in MeCN solution (1 ml) were then added. The solution washeated in a CEM Discover microwave at 90° C. (150 W, 250 psi) for atotal of 4 h. During this time, further palladium (II) acetate (4×3 mg,0.056 mmol) was added. The solvent was removed under a stream of N₂ andH₂O (3 ml) was added. The aqueous layer was extracted with EtOAc (3×1ml) and the organic layer washed with H₂O (1 ml), dried (MgSO₄),filtered and the solvent removed in vacuo. The residue was purified bycolumn chromatography eluting with 20% EtOAc in heptane to give thetitle compound.

Yield: 67 mg, 65%; LC/MS t_(r) 1.78 min; MS(ES+) m/z 368 (M+H).

(iii) 3-[3-(2-Phenyl-thiazol-4-ylmethylsulfanyl)-phenyl]-acrylic acid(122)

The ester (67 mg, 0.18 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 39 mg, 61%; LC/MS t_(r) 1.61 min; MS(ES+) m/z 354 (M+H); HPLCPurity: 100%; ¹H NMR (250 MHz; MeOD): δ 4.38 (s, 2H), 6.48 (d, 1H),7.25-7.53 (m, 7H), 7.57-7.70 (m, 2H), 7.89-7.99 (m, 2H).

(d) 3-{3-[(5-Adamantan-1-yl-furan-2-carbonyl)-amino]-phenyl}-acrylicacid (123) (i) 5-Adamantan-1-yl-furan-2-carboxylic acid methyl ester

Furan-2-carboxylic acid methyl ester (500 mg, 3.97 mmol) and1-bromo-adamantane (853 mg, 3.97 mmol) were dissolved inortho-dichlorobenzene (6 ml) and cooled to 0° C. before adding AlCl₂(1.06 g, 7.94 mmol) as a solid. The reaction mixture was allowed to warmup to room temperature, stirred for 4 h, then heated to 40° C. for 2 hand left standing at room temperature overnight. The reaction mixturewas cooled to 0° C. and quenched with H₂O (10 ml). The organic layer wasseparated and the aqueous layer was extracted with DCM (3×20 ml). Thecombined organic layers were dried (MgSO₄), filtered and the DCM removedin vacuo. The ortho-dichlorobenzene solution was loaded to a silica-gelcolumn and flushed with heptane (100 ml). The title compound was theneluted using a stepped gradient of 0-10% EtOAc in heptane.

Yield: 503 mg, 49%; LC/MS t_(r) 1.84 min; MS(ES+) m/z 261 (M+H).

(ii) 5-Adamantan-1-yl-furan-2-carboxylic acid

The ester (503 mg, 1.93 mmol) was dissolved in THF (3 ml) and 1M NaOH (3ml). The suspension was stirred at room temperature for 2 h. MeOH (3 ml)and 1M NaOH (3 ml) were added, and the suspension was heated to 40° C.for 1.5 h. THF and MeOH were removed in vacuo upon which a precipitateappeared. The solid was filtered, washed with 2M HCl (10 ml), and driedin vacuo to give the title compound.

Yield: 458 mg, 96%; LC/MS t_(r) 1.57 min; MS(ES+) m/z 288 (M+MeCN+H).

(iii) 3-{3-[(5-Adamantan-1-yl-furan-2-carbonyl)-amino]-phenyl}-acrylicacid ethyl ester

5-Adamantan-1-yl-furan-2-carboxylic acid (50 mg, 0.20 mmol) was coupledto aniline (60) (43 mg, 0.22 mmol) using Method D to give the titlecompound.

Yield: 84 mg, 100%; LC-MS t_(r)1.97 min; MS(ES+) m/z 420 (M+H).

(iv) 3-{3-[(5-Adamantan-1-yl-furan-2-carbonyl)-amino]-phenyl}-acrylicacid (123)

The ester (84 mg, 0.20 mmol) was dissolved in MeOH (2 ml), THF (2 ml)and 1M NaOH (4 ml). The suspension was heated to 40° C. for 1 h. THF andMeOH were removed in vacuo, the solution was acidified with 2M HCl (3ml) and extracted with DCM (3×2 ml). The organic layer was dried(MgSO₄), filtered and the solvent removed in vacuo. The solid wastriturated with DCM (2 ml) to give the title compound.

Yield: 35 mg, 45%; LC/MS t_(r) 2.29 min; MS(ES+) m/z 392 (M+H); HPLCPurity: 97%; ¹H NMR (250 MHz; DMSO) δ 1.52 (s, 6H), 1.72 (s, 6H), 1.82(s, 3H), 6.05 (s, 1H), 6.26 (d, 1H), 7.04 (d, 1H), 7.13-7.22 (m, 2H),7.34 (d, 1H), 7.54 (d, 1H), 7.72 (s, 1H), 9.72 (s, 1H), 12.25 (broad s,1H).

(e)3-(3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid (125) (i) 3-(3-Amino-phenyl)-propionic acid ethyl ester (124)

3-(3-Aminophenyl)propionic acid (250 mg, 1.52 mmol) was esterified withEtOH using Method A to give the title compound.

Yield: 260 mg, 89%; LC-MS t_(r) 0.78 min; MS(ES+) m/z 194 (M+H).

(ii)3-(3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid ethyl ester

Carboxylic acid (67) (58 mg, 0.26 mmol) was coupled to aniline (124) (50mg, 0.26 mmol) using Method C. The residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 62 mg, 60%; LC/MS t_(r) 1.72 min; MS(ES+) m/z 398, 400 (M+H).

(iii)3-(3-{[5-(3-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid (125)

The ester (62 mg, 0.16 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 42 mg, 71%; LC/MS t_(r) 1.53 min; MS(ES+) m/z 369, 371 (M+H);HPLC purity: 100%; ¹H NMR (400 MHz; DMSO): δ 2.51 (t, 2H), 2.79 (t, 2H),6.96 (d, 1H), 7.2-7.3 (m, 2H), 7.35 (d, 1H), 7.41 (d, 1H), 7.48 (t, 1H),7.54 (s, 1H), 7.59 (d, 1H), 7.90 (d, 1H), 8.07 (s, 1H), 10.15 (s, 1H).

(f)3-(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid (126) (i)3-(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid ethyl ester

Carboxylic acid (67) (67 mg, 0.26 mmol) was coupled to aniline (124) (50mg, 0.26 mmol) using Method C. The residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 65 mg, 58%; LC/MS t_(r) 1.86 min; MS(ES+) m/z 432, 434 (M+H).

(ii)3-(3-{[5-(3,5-Dichloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid (126)

The ester (65 mg, 0.15 mmol) was hydrolysed using Method H to give thetitle compound.

Yield: 46 mg, 76%; LC/MS t_(r) 1.64 min; MS(ES+) m/z 404, 406 (M+H);HPLC purity: 90%; ¹H NMR (400 MHz; DMSO): δ 2.55 (t, 2H), 2.83 (t, 2H),7.01 (d, 1H), 7.28 (t, 1H), 7.38 (d, 1H), 7.43 (d, 1H), 7.56 (s, 1H),7.60 (t, 2H), 8.11 (s, 2H), 10.23 (s, 1H).

(g) (3-{[5-(3,5-Difluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (127)

The furyl bromide (16) (100 mg, 0.30 mmol) was coupled to3,5-difluoro-phenylboronic acid (48 mg, 0.30 mmol) using Method E.During this reaction, hydrolysis occurred. The residue was extractedusing Work-up E1 to give the acid. The residue was purified by columnchromatography eluting with 20% heptane: 75% EtOAc: 5% AcOH to give thetitle compound.

Yield: 25 mg, 23%; LC/MS t_(r) 1.47 min; MS(ES+) m/z 358 (M+H); HPLCPurity: 92%; ¹H NMR (400 MHz; DMSO): δ 3.64 (s, 2H), 7.10 (d, 1H),7.31-7.41 (m, 2H), 7.44 (q, 2H), 7.68 (s, 1H), 7.75 (d, 1H), 7.87 (d,2H), 10.29 (s, 1H).

(h) (3-{[5-(3-fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-aceticacid (128)

The furyl bromide (16) (100 mg, 0.30 mmol) was coupled to3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. Duringthis reaction, hydrolysis occurred. The residue was extracted usingWork-up E1 to give the title compound.

Yield: 26 mg, 25%; LC/MS t_(r) 1.45 min; MS(ES+) m/z 339 (M+H); HPLCPurity: 91%; ¹H NMR (400 MHz; DMSO): δ 3.50 (s, 2H), 6.95 (d, 1H), 7.15(t, 1H), 7.20 (d, 1H), 7.24 (t, 1H), 7.32 (d, 1H), 7.46 (q, 1H), 7.56(s, 1H), 7.62 (d, 1H), 7.74 (d, 1H), 7.83 (d, 1H), 10.13 (s, 1H).

(i) (3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-aceticacid (129)

The pyridyl bromide (77) (44 mg, 0.12 mmol) was coupled to3-chloro-phenylboronic acid (20 mg, 0.13 mmol) using Method E. Duringthis reaction, hydrolysis occurred. The residue was extracted usingWork-up E1 to give the acid. The solid was further purified bypreparative HPLC to give the title compound.

Yield: 8 mg, 18%; LC/MS t_(r) 1.51 min; MS(ES+) m/z 367, 369 (M+H); HPLCPurity: 99%; ¹H NMR (400 MHz; DMSO): δ 3.63 (s, 2H), 7.09 (d, 1H), 7.37(t, 1H), 7.60 (m, 2H), 7.82 (m, 2H), 8.17 (m, 2H), 8.33 (m, 2H), 8.52(s, 1H), 10.60 (s, 1H).

(j)(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-aceticacid (130)

The pyridyl bromide (77) (44 mg, 0.12 mmol) was coupled to3,5-dichloro-phenylboronic acid (20 mg, 0.10 mmol) using Method E.During this reaction, hydrolysis occurred. The residue was extractedusing Work-up E1 to give the acid. The solid was further purified bypreparative HPLC to give the title compound.

Yield: 30 mg, 62%; LC/MS t_(r) 1.63 min; MS(ES+) m/z 401, 403 (M+H);HPLC Purity: 99%; ¹H NMR (400 MHz; DMSO): δ 3.60 (s, 2H), 7.07 (d, 1H),7.35 (t, 1H), 7.77 (m, 3H), 8.17 (m, 2H), 8.37 (d, 1H), 8.49 (s, 2H),10.64 (s, 1H).

(k)3-(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (132) (i) 6-(3,5-Dichloro-phenyl)-pyridine-2-carboxylic acid (131)

6-Bromo-pyridine-2-carboxylic acid (500 mg, 2.47 mmol) was coupled to3,5-dichloro-phenylboronic acid (473 mg, 2.47 mmol) acid using Method Fto give the title compound.

Yield: 400 mg, 60%; LC/MS t_(r) 1.47 min; MS(ES+) m/z 268, 270 (M+H).

(ii)3-(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (60) (40mg, 0.21 mmol) using Method D. The residue was triturated with TBME (3ml) to give the title compound.

Yield: 61 mg, 72%; LC/MS t_(r) 1.98 min; MS(ES+) m/z 441, 443 (M+H).

(iii)3-(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (132)

The ester (61 mg, 0.14 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 50 mg, 87%; LC/MS t_(r) 1.73 min; MS(ES+) m/z 412, 414 (M+H);HPLC Purity: 89%; ¹H NMR (250 MHz; DMSO): δ 6.44 (d, 1H), 7.17 (d, 1H),7.29 (d, 1H), 7.40 (t, 1H), 7.75 (s, 1H), 7.82 (d, 1H), 8.02 (s, 1H),8.18 (d, 2H), 8.38 (q, 1H), 8.50 (s, 2H), 10.66 (s, 1H).

(l)(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (133) (i)(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid ethyl ester

Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (64) (40mg, 0.21 mmol) using Method D. The residue was triturated with TBME (3ml) to give the title compound.

Yield: 29 mg, 34%; LC/MS t_(r) 1.86 min; MS(ES+) m/z 445, 447 (M+H).

(ii)(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (133)

The ester (29 mg, 0.07 mmol) was hydrolysed using Method M. The solidwas triturated with DCM (3 ml) to give the title compound.

Yield: 27 mg, 100%; LC/MS t_(r) 1.67 min; MS(ES+) m/z 416, 418 (M+H);HPLC Purity: 92%; ¹H NMR (250 MHz; DMSO): δ 3.82 (s, 2H), 6.07 (broad s,1H), 6.85 (broad t_(r) 3H), 7.50 (s, 1H), 7.78 (m, 4H), 8.11 (broad s,1H), 8.32 (s, 1H).

(m)3-(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-propionicacid (134) (i)3-(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-propionicacid ethyl ester

Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (124)(40 mg, 0.21 mmol) using Method D to give the product, which was usedwithout further purification.

Yield: 83 mg, 99%; LC/MS t_(r) 1.90 min; MS(ES+) m/z 443, 445 (M+H).

(ii)3-(3-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-propionicacid (134)

The ester (83 mg, 0.19 mmol) was hydrolysed using Method M. The residuewas purified by preparative HPLC to give the title compound.

Yield: 42 mg, 53%; LC/MS t_(r) 1.66 min; MS(ES+) m/z 415, 417 (M+H);HPLC Purity: 96%; ¹H NMR (400 MHz; DMSO): δ 2.69 (t, 2H), 2.98 (t, 2H),7.16 (d, 1H), 7.44 (t, 1H), 7.80-7.88 (m, 3H), 8.25-8.32 (m, 2H), 8.47(d, 1H), 8.59 (s, 2H), 10.70 (s, 1H), 12.28 (s, 1H).

(n)5-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-1H-indole-2-carboxylicacid (135) (i)5-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-1H-indole-2-carboxylicacid ethyl ester

Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (58) (42mg, 0.21 mmol) using Method D to give the crude product.

Yield: 85 mg, 99%; LC/MS t_(r) 1.82 min; MS(ES+) m/z 454, 456 (M+H).

(ii)5-{[6-(3,5-Dichloro-phenyl)-pyridine-2-carbonyl]-amino}-1H-indole-2-carboxylicacid (135)

The ester (85 mg, 0.19 mmol) was hydrolysed using Method M. The residuewas purified by preparative HPLC to give the title compound.

Yield: 16 mg, 20%; LC/MS t_(r) 1.61 min; MS(ES+) m/z 426, 428 (M+H);HPLC Purity: 99%; ¹H NMR (400 MHz; DMSO): δ 7.23 (s, 1H), 7.56 (d, 1H),7.75 (dd, 1H), 7.85 (t, 1H), 8.27 (m, 3H), 8.47 (q, 1H), 8.61 (d, 2H),10.73 (s, 1H).

(o)3-(3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (137) (i) 6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (136)

6-Bromo-pyridine-2-carboxylic acid (200 mg, 0.99 mmol) was coupled to3-chloro-phenylboronic acid (130 mg, 0.83 mmol) using Method F to givethe title compound.

Yield: 182 mg, 98%; LC/MS t_(r) 1.32 min; MS(ES+) m/z 234, 236 (M+H).

(ii)3-(3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

Carboxylic acid (136) (44 mg, 0.19 mmol) was coupled with aniline (60)(40 mg, 0.21 mmol) using Method D. The residue was purified by columnchromatography eluting with a stepped gradient of 10-15% EtOAc inheptane to give the title compound.

Yield: 64 mg, 83%; LC/MS t_(r) 1.87 min; MS(ES+) m/z 407, 409 (M+H).

(iii)3-(3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (137)

The ester (64 mg, 0.16 mmol) was hydrolysed using Method M. The residuewas purified by preparative HPLC to give the title compound.

Yield: 7 mg, 11%; LC/MS t_(r) 1.98 min; MS(ES+) m/z 379, 381 (M+H); HPLCPurity: 97%; ¹H NMR (250 MHz; DMSO): δ 6.54 (d, 1H), 7.43-7.67 (m, 5H),7.99 (d, 1H), 8.17 (m, 3H), 8.34 (m, 2H), 8.50 (s, 1H), 10.66 (s, 1H).

(p) (3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (138) (i)(3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid ethyl ester

Carboxylic acid (136) (44 mg, 0.19 mmol) was coupled with aniline (64)(40 mg, 0.2 mmol) using Method D. The residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 50 mg, 64%; LC/MS t_(r) 1.77 min; MS(ES+) m/z 411, 413 (M+H).

(ii)(3-{[6-(3-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (138)

The ester (50 mg, 0.12 mmol) was hydrolysed using Method M. The residuewas purified by preparative HPLC to give the title compound.

Yield: 30 mg, 65%; LC/MS t_(r) 1.51 min; MS(ES+) m/z 383, 385 (M+H);HPLC Purity: 99%; ¹H NMR (400 MHz; DMSO): δ 4.63 (s, 2H), 6.66 (dd, 1H),7.24 (t, 1H), 7.44 (d, 1H), 7.53 (m, 3H), 8.03 (m, 2H), 8.25 (m, 2H),8.41 (s, 1H), 10.49 (s, 1H).

(q) {3-[(3′-Chloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-aceticacid (140) (i) [3-(5-Bromo-2-fluoro-benzoylamino)-phenoxy]-acetic acidethyl ester (139)

5-Bromo-2-fluoro-benzoic acid (250 mg, 1.14 mmol) was coupled to aniline(64) (245 mg, 1.25 mmol) using Method D. The residue was purified bycolumn chromatography eluting with a stepped gradient of 10-15% EtOAc inheptane to give the title compound.

Yield: 144 mg, 36%; LC/MS t_(r) 1.52 min; MS(ES+) m/z 396, 398 (M+H).

(ii) {3-[(3′-Chloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-aceticacid (140)

The phenyl bromide (139) (50 mg, 0.13 mmol) was coupled to3-chloro-phenylboronic acid (20 mg, 0.13 mmol) using Method E. Duringthis reaction, hydrolysis occurred and the residue was extracted usingWork-up E1. The crude product was then triturated with TBME (2 ml), DCM(2 ml), and recrystallised from a hot 10% EtOH in H₂O mixture to givethe title compound.

Yield: 2 mg, 4%; LC/MS t_(r) 1.89 min; MS(ES+) m/z 400, 402 (M+H); HPLCPurity: 88%; ¹H NMR (400 MHz; DMSO) δ 3.95 (s, 2H), 6.45 (d, 1H), 7.10(m, 2H), 7.20 (m, 1H), 7.30-7.50 (m, 3H), 7.65 (d, 1H), 7.75 (e, 1H),7.80 (m, 1H), 7.90 (d, 1H), 10.35 (s, 1H).

(r)3-{3-[(3′-Chloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid (142) (i) 3-[3-(5-Bromo-2-fluoro-benzoylamino)-phenyl]-acrylic acidethyl ester (141)

5-Bromo-2-fluoro-benzoic acid (250 mg, 1.14 mmol) was coupled to aniline(60) (240 mg, 1.26 mmol) using Method D. The residue was purified bycolumn chromatography eluting with a stepped gradient of 10-15% EtOAc inheptane to give the title compound.

Yield: 402 mg, 90%; LC/MS t_(r) 1.64 min; MS(ES+) m/z 392, 394 (M+H).

(ii)3-{3-[(3′-Chloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid ethyl ester

The phenyl bromide (141) (100 mg, 0.26 mmol) was coupled to3-chloro-phenylboronic acid (40 mg, 0.26 mmol) using Method E. Theresidue was purified by column chromatography eluting with 10% EtOAc inheptane to give the title compound.

Yield: 109 mg, 99%; LC/MS t_(r) 1.82 min; MS(ES+) m/z 424, 426 (M+H).

(iii)3-{3-[(3′-Chloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid (142)

The ester (109 mg, 0.26 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 80 mg, 78%; LC/MS t_(r) 1.05 min; MS(ES+) m/z 396, 398 (M+H);HPLC Purity: 95%; ¹H NMR (400 MHz, DMSO): δ 6.60 (d, 1H), 7.40-7.75 (m,6H), 7.90 (d, 2H), 8.00 (s, 1H), 8.10 (broad s, 2H), 8.20 (d, 1H), 10.80(s, 1H).

(s){3-[(3′,5′-Dichloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-aceticacid (143) (i){3-[(3′,5′-Dichloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-aceticacid ethyl ester

The phenyl bromide (139) (50 mg, 0.13 mmol) was coupled to3,5-dichloro-phenylboronic acid (24 mg, 0.13 mmol) using method E. Theresidue was purified by column chromatography eluting with 10% EtOAc inheptane to give the title compound.

Yield: 10 mg, 17%; LC/MS t_(r)1.79 min; MS(ES+) m/z 462, 464 (M+H).

(ii){3-[(3′,5′-Dichloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-aceticacid (143)

The ester (10 mg, 0.02 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 4 mg, 46%; LC/MS t_(r)1.09 min; MS(ES+) m/z 434, 436 (M+H); HPLCPurity: 91%; ¹H NMR (400 MHz; DMSO) δ 4.50 (s, 2H), 6.65 (d, 1H), 7.20(t, 1H), 7.30 (broad s, 2H), 7.45 (t, 1H), 7.65 (s, 1H), 7.85 (s, 2H),8.00 (m, 1H), 8.05 (d, 1H), 10.50 (s, 1H).

(t)3-{3-[(3′,5′-Dichloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid (144) (i)3-{3-[(3′,5′-Chloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid ethyl ester

The phenyl bromide (141) (100 mg, 0.26 mmol) was coupled to3,5-dichloro-phenylboronic acid (40 mg, 0.21 mmol) using method E. Theresidue was purified by column chromatography eluting with 10% EtOAc inheptane to give the title compound.

Yield: 75 mg, 78%; LC/MS t_(r)1.90 min; MS(ES+) m/z 458, 460 (M+H).

(ii)3-{3-[(3′,5′-Chloro-4-fluoro-biphenyl-3-carbonyl)-amino]-phenyl}-acrylicacid (144)

The ester (75 mg, 0.16 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 58 mg, 84%; LC/MS t_(r) 1.66 min; MS(ES+) m/z 430, 432 (M+H);HPLC Purity: 89%; ¹H NMR (400 MHz, DMSO): δ 6.50 (d, 1H), 7.35-7.70 (m,5H), 7.80 (d, 1H), 7.90 (s, 2H), 8.00 (broad s, 2H), 8.10 (m, 1H), 10.60(s, 1H).

(u) 3-(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid (146) (i) 5-(4-Chloro-phenyl)-furan-2-carboxylic acid (145)

5-Bromo-2-furoic acid (1 g, 5.25 mmol) was coupled to4-chloro-phenylboronic acid (819 mg, 5.23 mmol) acid using Method E togive the title compound.

Yield: 250 mg, 22%; LC/MS t_(r) 1.34 min; MS(ES+) m/z 223, 225 (M+H). ¹HNMR (400 MHz, DMSO): δ 7.05 (d, 1H), 7.20 (d, 1H), 7.40 (d, 2H), 7.70(d, 2H).

(ii) 3-(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

Carboxylic acid (145) (50 mg, 0.19 mmol) was coupled to aniline (60) (43mg, 0.23 mmol) using Method C. The residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 66 mg, 87%; LC/MS t_(r) 1.77 min; MS(ES+) m/z 396, 398 (M+H).

(iii)3-(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-acrylic acid(146)

The ester (66 mg, 0.17 mmol) was hydrolysed using Method M. The residuewas recrystallised from a hot 10% EtOH in H₂O mixture to give the titlecompound.

Yield: 40 mg, 64%; LC/MS t_(r) 1.49 min; MS(ES+) m/z 368, 370 (M+H);HPLC Purity: 100%; ¹H NMR (400 MHz, DMSO): δ 6.50 (d, 1H), 7.30 (d, 1H),7.35-7.65 (m, 6H), 7.85 (m, 1H), 8.00 (m, 3H).

(v)3-(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid (147) (i)3-(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid ethyl ester

Carboxylic acid (145) (58 mg, 0.26 mmol) was coupled to aniline (124)(50 mg, 0.26 mmol) using Method C. During this reaction, partialhydrolysis occurred. The acid was re-dissolved in EtOAc (2 ml) and theorganic layer was washed with 1M HCl (2×1 ml), dried (Na₂SO₄), filteredand the solvent removed in vacuo to give a mixture of acid and ester,which was used without further purification.

For the ester: LC/MS t_(r) 1.72 min; MS(ES+) m/z 398, 400 (M+H).

(ii)3-(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid (147)

The mixture (103 mg, 0.26 mmol) was hydrolysed using Method M. The solidwas recrystallised from a hot 10% EtOH in H₂O mixture to give the titlecompound.

Yield: 40 mg, 41% over 2 steps; LC/MS t_(r) 1.48 min; MS(ES+) m/z 370,372 (M+H); HPLC Purity: 100%; ¹H NMR (400 MHz, DMSO): δ 2.60 (t, 2H),2.90 (t, 2H), 7.00 (d, 1H), 7.20-7.35 (m, 2H), 7.40 (1H), 7.50-7.70 (m,4H), 8.05 (d, 2H), 10.20 (s, 1H).

(x)3-(3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid (148)

Carboxylic acid (76) (53 mg, 0.26 mmol) was coupled to aniline (124) (50mg, 0.26 mmol) using Method C. During this reaction, hydrolysisoccurred. The acid was re-dissolved in EtOAc (2 ml) and the organiclayer was washed with 1M HCl (2×1 ml), dried (Na₂SO₄), filtered and thesolvent removed in vacuo. The solid was recrystallised from a hot 10%EtOH in H₂O mixture to give the title compound.

Yield: 40 mg, 43%; LC/MS t_(r) 1.39 min; MS(ES+) m/z 354 (M+H); HPLCPurity: 93%; ¹H NMR (400 MHz, DMSO): δ 2.57 (t, 2H), 2.85 (t, 2H), 7.01(d, 1H), 7.17 (d, 1H), 7.24-7.42 (m, 4H), 7.63 (t, 2H), 8.05 (2H), 10.14(s, 1H).

(y) (3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-aceticacid (150) (i) 6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid (149)

6-Bromo-pyridine-2-carboxylic acid (1 g, 4.95 mmol) was coupled to4-chloro-phenylboronic acid (775 mg, 4.96 mmol) acid using Method F togive the title compound.

Yield: 900 mg, 78%; LC/MS t_(r) 1.29 min; MS(ES+) m/z 234, 236 (M+H); ¹HNMR (400 MHz, DMSO): δ 7.50 (d, 2H), 8.00 (t, 1H), 8.05 (d, 1H), 8.15(t, 3H).

(ii) (3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-aceticacid ethyl ester

Carboxylic acid (149) (50 mg, 0.22 mmol) was coupled to aniline (6) (39mg, 0.22 mmol) using Method C. The residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 28 mg, 32%; LC/MS t_(r) 1.77 min; MS(ES+) m/z 395, 397 (M+H).

(iii)(3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acetic acid(150)

The ester (28 mg, 0.07 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 17 mg, 66%; LC/MS t_(r) 1.54 min; MS(ES+) m/z 367, 369 (M+H);HPLC Purity: 99%; ¹H NMR (250 MHz; DMSO): δ 3.60 (s, 2H), 7.10 (d, 1H),7.40 (t, 1H), 7.60 (d, 2H), 7.80 (s, 2H), 8.10-8.20 (m, 2H), 8.30 (d,1H), 8.45 (d, 2H).

(z)3-(3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (151) (i)3-(3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

Carboxylic acid (149) (50 mg, 0.21 mmol) was coupled to aniline (60) (41mg, 0.21 mmol) using Method C. The residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 34 mg, 40%; LC/MS t_(r) 1.88 min; MS(ES+) m/z 407, 409 (M+H).

(ii)3-(3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (151)

The ester (34 mg, 0.08 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 15 mg, 50%; LC/MS t_(r) 1.62 min; MS(ES+) m/z 379, 381 (M+H);HPLC Purity: 99%; ¹H NMR (250 MHz; DMSO): δ 6.60 (d, 1H), 7.45-7.60 (m,2H), 7.60-7.70 (m, 3H), 8.05 (m, 1H), 8.10-8.25 (m, 3H), 8.35 (m, 1H),8.50 (d, 2H), 10.65 (s, 1H).

(aa) (3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-aceticacid (153) (i) 6-(4-Fluoro-phenyl)-pyridine-2-carboxylic acid (152)

6-Bromo-pyridine-2-carboxylic acid (1 g, 4.95 mmol) was coupled4-fluoro-phenylboronic acid (693 mg, 4.95 mmol) acid using Method F togive the title compound.

Yield: 900 mg, 83%; LC/MS t_(r) 1.14 min; MS(ES+) m/z 218 (M+H); ¹H NMR(400 MHz, DMSO): δ 7.42 (t, 2H), 8.05 (d, 1H), 8.13 (t, 1H), 8.27 (d,1H), 8.32 (t, 2H).

(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acetic acidethyl ester

Carboxylic acid (152) (50 mg, 0.23 mmol) was coupled to aniline (6) (42mg, 0.23 mmol) using Method C. The residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 53 mg, 61%; LC/MS t_(r) 1.69 min; MS(ES+) m/z 379 (M+H).

(iii)(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acetic acid(153)

The ester (48 mg, 0.13 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 40 mg, 88%; LC/MS t_(r) 1.46 min; MS(ES+) m/z 351 (M+H); HPLCPurity: 99%; ¹H NMR (250 MHz; DMSO): δ 3.60 (s, 2H), 7.31-7.43 (m, 3H),7.81 (d, 2H), 8.07-8.18 (2H), 8.25 (d, 2H), 8.45 (m, 2H), 10.52 (s, 1H).

(bb)(3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (154) (i)(3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid ethyl ester

Carboxylic acid (149) (50 mg, 0.21 mmol) was coupled to aniline (64) (42mg, 0.21 mmol) using Method C. During this reaction, partial hydrolysisoccurred. The residue was re-dissolved in EtOAc (2 ml) and the organiclayer was washed with 1M HCl (2×1 ml), dried (Na₂SO₄), filtered and thesolvent removed in vacuo to give a mixture of acid and ester, which wasused without further purification.

For the ester: LC/MS t_(r) 1.76 min; MS(ES+) m/z 411, 413 (M+H).

(ii)(3-{[6-(4-Chloro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (154)

The mixture (86 mg, 0.21 mmol) was hydrolysed using Method M. Theresidue was purified by column chromatography eluting with 47.5% EtOAc:47.5% heptane: 5% AcOH to give the title compound.

Yield: 3 mg, 4% over 2 steps; LC/MS t_(r) 1.55 Min; MS(ES+) m/z 383, 385(M+H); ¹H NMR (250 MHz; DMSO): δ 4.70 (s, 2H), 6.70 (d, 1H), 7.30 (t,1H), 7.50 (d, 1H), 7.60 (m, 3H), 8.10-8.35 (m, 3H), 8.45 (d, 2H).

(cc)3-(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (155) (i)3-(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid ethyl ester

Carboxylic acid (152) (50 mg, 0.23 mmol) was coupled to aniline (60) (44mg, 0.23 mmol) using Method C. The crude residue was purified by columnchromatography eluting with 10% EtOAc in heptane to give the titlecompound.

Yield: 78 mg, 871; LC/MS t_(r) 1.79 min; MS(ES+) m/z 391 (M+H).

(ii)3-(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-acrylicacid (155)

The ester (65 mg, 0.17 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 54 mg, 88%; LC/MS t_(r) 1.53 min; MS(ES+) m/z 363 (M+H); HPLCPurity: 99%; ¹H NMR (250 MHz; DMSO): δ 6.44 (d, 1H), 7.13 (d, 1H), 7.26(d, 1H), 7.40 (m, 3H), 7.86 (d, 1H), 8.01 (s, 1H), 8.08-8.30 (m, 3H),8.47 (m, 2H), 10.55 (s, 1H).

(dd) (3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (156) (i)(3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-acetic acidethyl ester

Carboxylic acid (145) (57 mg, 0.26 mmol) was coupled to aniline (64) (50mg, 0.26 mmol) using Method C to give the title compound.

Yield: 61 mg, 59%; LC/MS t_(r) 1.64 min; MS(ES+) m/z 400, 402 (M+H).

(ii) (3-{[5-(4-Chloro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (156)

The ester (61 mg, 0.15 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 42 mg, 75%; LC/MS t_(r) 1.50 min; MS(ES+) m/z 372, 374 (M+H);HPLC Purity: 100%; ¹H NMR (400 MHz, DMSO) δ 4.14 (s, 2H), 6.57-6.60 (m,1H), 7.17-7.24 (m, 2H), 7.30-7.33 (m, 2H), 7.45 (d, 1H) 7.57-7.60 (m,2H), 8.01-8.03 (m, 2H), 10.25 (s, 1H).

(ee) (3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (157) (i)(3-{[5-(4-fluoro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-acetic acidethyl ester

Carboxylic acid (76) (53 mg, 0.26 mmol) was coupled to aniline (64) (56mg, 0.26 mmol) using Method C to give the title compound.

Yield: 40 mg, 40%; LC/MS t_(r) 1.54 min; MS(ES+) m/z 384 (M+H).

(ii) (3-{[5-(4-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (157)

The ester (40 mg, 0.10 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 20 mg, 54%; LC/MS t_(r) 1.44 min; MS(ES+) m/z 356 (M+H); HPLCPurity: 98%; ¹H NMR (250 MHz, DMSO) δ 4.68 (s, 2H), 6.67-6.71 (m, 1H),7.14-7.45 (m, 7H), 8.01-8.05 (m, 2H).

(ff)(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (158) (i)(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid ethyl ester

Carboxylic acid (152) (50 mg, 0.23 mmol) was coupled to aniline (64) (45mg, 0.23 mmol) using Method C to give the title compound.

Yield: 35 mg, 39%; LC/MS t_(r) 1.67 min; MS(ES+) m/z 395 (M+H).

(ii)(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (158)

The ester (35 mg, 0.09 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 17 mg, 52%; LC/MS t_(r) 1.45 min; MS(ES+) m/z 367 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO) δ 4.71 (s, 2H), 6.72-6.75 (m, 1H),7.30-7.42 (m, 3H), 7.52-7.54 (m, 1H), 7.62 (s, 1H), 8.10-8.18 (m, 2H),8.25-8.27 (m, 1H), 8.44-8.48 (m, 2H), 10.52 (s, 1H), 13.06 (s, 1H).

(gg)3-(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]amino}-phenyl)-propionicacid (159) (i)3-(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]amino}-phenyl)-propionicacid ethyl ester

Carboxylic acid (152) (50 mg, 0.23 mmol) was coupled to aniline (124)(45 mg, 0.23 mmol) using Method C. The residue was purified by columnchromatography eluting with 30% EtOAc in heptane to give the titlecompound.

Yield: 11 mg, 12%; LC/MS t_(r) 1.77 min; MS(ES+) m/z 393 (M+H).

(j)3-(3-{[6-(4-Fluoro-phenyl)-pyridine-2-carbonyl]amino}-phenyl)-propionicacid (159)

The ester (11 mg, 0.028 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 5 mg, 49%; LC/MS t_(r) 1.49 min; MS(ES+) m/z 365 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO) δ 2.59 (t, 2H), 2.88 (t, 2H), 7.05(d, 1H), 7.31-7.43 (m, 3H), 7.76-7.80 (m, 2H), 8.10-8.18 (m, 2H),8.25-8.27 (m, 1H), 8.45-8.48 (m, 2H), 10.49 (s, 1H), 12.19 (s, 1H).

(hh) {3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenoxy}-acetic acid (160)(i) {3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenoxy}-acetic acid ethylester

Carboxylic acid (56) (50 mg, 0.27 mmol) was coupled to aniline (64) (52mg, 0.27 mmol) using Method C. During this reaction, partial hydrolysisoccurred. The residue was re-dissolved in EtOAc (2 ml) and the organiclayer was washed with 1M HCl (2×1 ml), dried (Na₂SO₄), filtered and thesolvent removed in vacuo to give a mixture of acid and ester, which wasused without further purification.

For the ester: LC/MS t_(r) 1.47 min; MS(ES+) m/z 352 (M+H).

(ii) {3-[(5-Phenyl-furan-2-carbonyl)-amino]-phenoxy}-acetic acid (160)

The mixture (95 mg, 0.27 mmol) was hydrolysed using Method M. The solidwas recrystallised from a hot 10% EtOH in H₂O mixture and trituratedwith DCM (2 ml) to give the title compound.

Yield: 20 mg, 22% over 2 steps; LC/MS t_(r) 1.35 min; MS(ES+) m/z 338(M+H); HPLC Purity: 93%; ¹H NMR (400 MHz, DMSO) δ 4.70 (s, 2H),6.69-6.72 (m, 1H), 7.21-7.31 (m, 2H), 7.41-7.55 (m, 6H), 7.99-8.01 (m,2H), 10.18 (s, 1H), 13.10 (s, 1H).

(ii)3-(3-{[6-(3-Fluoro-Phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-propionicacid (162) (i)3-{3-[(6-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-propionic acid ethylester (161)

6-Bromo-pyridine-2-carboxylic acid (261 mg, 1.29 mmol) was coupled toaniline (124) (250 mg, 1.29 mmol) using Method C to give the titlecompound.

Yield: 308 mg, 63%; LC/MS t_(r) 1.58 min; MS(ES+) m/z 377, 379 (M+H).

(ii)3-(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-propionicacid ethyl ester

The pyridyl bromide (161) (100 mg, 0.27 mmol) was coupled to3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. Theresidue was purified by column chromatography eluting with 15% EtOAc inheptane to give the title compound.

Yield: 75 mg, 80%; LC-MS t_(r) 1.72 min; MS(ES+) m/z 393 (M+H).

(iii)3-(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenyl)-propionicacid (162)

The ester (75 mg, 0.19 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 60 mg, 87%; LC/MS t_(r) 1.49 min; MS(ES+) m/z 365 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO) δ 2.59 (t, 2H), 2.88 (t, 2H), 7.06(d, 1H), 7.31-7.39 (m, 2H), 7.59-7.64 (m, 1H), 7.76-7.80 (m, 2H),8.14-8.19 (m, 3H), 8.30-8.36 (m, 2H), 10.52 (s, 1H), 12.21 (s, 1H).

(jj)3-(3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid (163) (i) 3-{3-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-propionicacid ethyl ester

5-Bromo-2-furoic acid (247 mg, 1.29 mmol) was coupled to aniline (124)(250 mg, 1.29 mmol) using Method C to give the title compound.

Yield: 247 mg, 52%; LC/MS t_(r) 1.46 min; MS(ES+) m/z 366, 368 (M+H).

(ii)3-(3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid ethyl ester

The furyl bromide (100 mg, 0.27 mmol) was coupled to3-fluoro-phenylboronic (35 mg, 0.25 mmol) acid using Method E. Theresidue Was purified by column chromatography eluting with 15% EtOAc inheptane to give the title compound.

Yield: 77 mg, 81%; LC-MS t_(r) 1.62 min; MS(ES+) m/z 382 (M+H).

(iii)3-(3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenyl)-propionicacid (163)

The ester (77 mg, 0.20 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 67 mg, 95%; LC/MS t_(r) 1.41 min; MS(ES+) m/z 354 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO) δ 2.58 (t, 2H), 2.86 (t, 2H), 7.02(d, 1H), 7.23-7.32 (m, 3H), 7.41 (d, 1H), 7.53-7.66 (m, 3H), 7.84 (d,1H), 7.91-7.95 (m, 1H), 10.52 (s, 1H), 12.21 (s, 1H).

(kk) 3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-propionic acid(164) (i) 3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-propionicacid ethyl ester

The pyridyl bromide (161) (100 mg, 0.27 mmol) was coupled tophenylboronic acid (30 mg, 0.25 mmol) using Method E. The residue waspurified by column chromatography eluting with 15% EtOAc in heptane togive the title compound.

Yield: 55 mg, 59%; LC-MS t_(r) 1.73 min; MS(ES+) m/z 375 (M+H).

(ii) 3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-propionic acid(164)

The ester (55 mg, 0.15 mmol) was hydrolysed using Method M to give thetitle compound.

Yield: 16 mg, 31%; LC/MS t_(r) 1.46 min; MS(ES+) m/z 347 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO) δ 2.59 (t, 2H), 2.88 (t, 2H), 7.05(d, 1H), 7.31-7.35 (m, 1H), 7.51-7.61 (m, 3H), 7.77-7.80 (m, 2H),8.11-8.18 (m, 2H), 8.25-8.28 (m, 1H), 8.37-8.39 (m, 2H), 10.48 (s, 1H),12.19 (s, 1H).

(ll) 3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid (165)(i) 3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid ethylester

The phenyl bromide (139) (100 mg, 0.25 mmol) was coupled tophenylboronic acid (28 mg, 0.23 mmol) using Method E. During thisreaction, partial hydrolysis occurred. The residue was extracted usingWork-up E1 to give a mixture of acid and ester, which was used withoutfurther purification.

For the ester: LC/MS t_(r) 1.61 min; MS(ES+) m/z 394 (M+H).

(ii) 3-[(4-Fluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid (165)

The mixture (90 mg, 0.23 mmol) was hydrolysed using Method M. Theresidue was triturated with TBME (2 ml) to give the title compound.

Yield: 41 mg, 49% over 2 steps; LC/MS t_(r) 1.51 min; MS(ES+) m/z 366(M+H); HPLC Purity: 92%; ¹H NMR (250 MHz, DMSO) δ 4.66 (s, 2H),6.66-6.71 (d, 1H), 7.23-7.53 (m, 7H), 7.73-7.76 (m, 2H), 7.85-7.93 (m,2H), 10.52 (s, 1H).

(mm) 3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-propionic acid(167) (i) {3-[(6-Bromo-pyridine-2-carbonyl)-amino]-phenoxy}-acetic acidethyl ester (166)

6-Bromo-pyridine-2-carboxylic acid (250 mg, 1.24 mmol) was coupled toaniline (64) (241 mg, 1.24 mmol) using Method C to give the titlecompound.

Yield: 387 mg, 82%; LC/MS t_(r) 1.49 min; MS(ES+) m/z 379, 381 (M+H).

(ii) 3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-propionic acid(167)

Bromo-derivative (166) (100 mg, 0.26 mmol) was coupled to phenylboronic(30 mg, 0.25 mmol) acid using Method E. During this reaction, hydrolysisoccurred. The residue was extracted using Work-up E1 and triturated withTBME (2 ml) to give the title compound.

Yield: 48 mg, 55%; LC/MS t_(r) 1.42 min; MS(ES+) m/z 349 (M+H); HPLCPurity: 100%; ¹H NMR (400 MHz, DMSO) δ 4.71 (s, 2H), 6.72-6.75 (m, 1H),7.29-7.34 (m, 1H), 7.52-7.63 (m, 5H), 8.10-8.18 (m, 2H), 8.25-8.28 (m,1H), 8.36-8.38 (m, 2H), 10.51 (s, 1H), 13.07 (s, 1H).

(nn) (3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (168) (i) {3-[(5-Bromo-furan-2-carbonyl)-amino]-phenoxy}-aceticacid ethyl ester

5-Bromo-furan-2-carboxylic acid (245 mg, 1.28 mmol) was coupled toaniline (64) (250 mg, 1.28 mmol) using Method C. The residue waspurified by column chromatography eluting with 15% EtOAc in heptane togive the title compound.

Yield: 360 mg, 76%; LC/MS t_(r) 1.41 min; MS(ES+) m/z 368, 370 (M+H).

(ii) (3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid ethyl ester

The furyl bromide (100 mg, 0.27 mmol) was coupled to3-fluoro-phenylboronic acid (35 mg, 0.25 mmol) using Method E. Duringthis reaction, partial hydrolysis occurred. The residue was extractedusing Work-up E1 to give a mixture of acid and ester, which was usedwithout further purification.

For the ester: LC/MS t_(r) 1.57 min; MS(ES+) m/z 384 (M+H).

(iii) (3-{[5-(3-Fluoro-phenyl)-furan-2-carbonyl]-amino}-phenoxy)-aceticacid (168)

The mixture (95 mg, 0.25 mmol) was hydrolysed using Method M. Theresidue was triturated with TBME (2 ml) to give the title compound.Yield: 71 mg, 80% over 2 steps; LC/MS t_(r) 1.43 min; MS(ES+) m/z 356(M+H); HPLC Purity: 100%; ¹H NMR (250 MHz, DMSO): δ 4.69 (s, 2H), 6.70(d, 1H), 7.19-7.33 (m, 3H), 7.36-7.47 (m, 3H), 7.51-7.61 (m, 1H),7.81-7.96 (m, 2H), 10.20 (s, 1H).

(oo) {3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid(169) (i) {3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-aceticacid ethyl ester

The phenyl bromide (139) (100 mg, 0.25 mmol) was coupled to3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. Duringthis reaction, partial hydrolysis occurred. The residue was extractedusing Work-up E1 to give a mixture of acid and ester, which was usedwithout further purification.

For the ester: LC/MS t_(r) 1.62 min; MS(ES+) m/z 412 (M+H).

(ii) {3-[(4,3′-Difluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid(169)

The mixture (99 mg, 0.24 mmol) was hydrolysed using Method M. Theresidue was triturated with TBME (2 ml) to give the title compound.Yield: 30 mg, 33% over 2 steps; LC/MS t_(r) 1.54 min; MS(ES+) m/z 384(M+H); HPLC Purity: 100%; ¹H NMR (250 MHz, DMSO): δ 4.47 (s, 2H), 6.64(d, 1H), 7.19-7.29 (m, 2H), 7.31-7.39 (m, 2H), 7.41-7.67 (m, 4H),7.88-8.01 (m, 2H), 10.49 (s, 1H).

(pp)(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (170) (i)(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid ethyl ester

The pyridyl bromide (166) (100 mg, 0.26 mmol) was coupled to3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. Duringthis reaction, partial hydrolysis occurred. The residue was extractedusing Work-up E1 to give a mixture of acid and ester, which was usedwithout further purification.

For the ester: LC/MS t_(r) 1.43 min; MS(ES+) m/z 395 (M+H).

(ii)(3-{[6-(3-Fluoro-phenyl)-pyridine-2-carbonyl]-amino}-phenoxy)-aceticacid (170)

The mixture (94 mg, 0.24 mmol) was hydrolysed using Method M. Theresidue was triturated with TBME (2 ml) to give the title compound.Yield: 88 mg, 100% over 2 steps; LC/MS t_(r) 1.43 min; MS(ES+) m/z 367(M+H); HPLC Purity: 97%; ¹H NMR (250 MHz, DMSO): δ 4.49 (s, 2H), 6.51(d, 1H), 7.06-7.18 (m, 2H), 7.27-7.46 (m, 3H), 7.89-7.99 (m, 3H),8.04-8.12 (m, 2H), 10.32 (s, 1H).

(qq) {3-[(4,4′-Difluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid(171) (i) {3-[(4,4′-Difluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-aceticacid ethyl ester

The phenyl bromide (139) (100 mg, 0.25 mmol) was coupled to4-fluoro-phenylboronic acid (33 mg, 0.23 mmol) using Method E. Duringthis reaction, partial hydrolysis occurred. The residue was extractedusing Work-up E1 to give a mixture of acid and ester, which was usedwithout further purification.

For the ester: LC/MS t_(r) 1.62 min; MS(ES+) m/z 412 (M+H).

(ii) {3-[(4,4′-Difluoro-biphenyl-3-carbonyl)-amino]-phenoxy}-acetic acid(171)

The mixture (95 mg, 0.23 mmol) was hydrolysed using Method M. Theresidue was triturated with TBME (2 ml) to give the title compound.Yield: 32 mg, 36% over 2 steps; LC/MS t_(r) 1.53 min; MS(ES+) m/z 384(M+H); HPLC Purity: 97%; ¹H NMR (250 MHz, DMSO): δ 4.67 (s, 2H), 6.69(d, 7.21-7.50 (m, 6H), 7.74-7.93 (m, 4H), 10.51 (s, 1H).

(rr) 3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-acrylic acid(178) (i) 3-{3-[(6-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-acrylicacid ethyl ester

Aniline (60) (124 mg, 0.6 mmol) was coupled to6-bromo-pyridine-2-carboxylic acid (131 mg, 0.6 mmol) using Method C.The residue was purified by column chromatography eluting in 10% EtOAcin heptane to give the title compound.

Yield: 25 mg, 11%; LC/MS t_(r) 1.61 min; MS(ES+) m/z 375, 377 (M+).

(ii) 3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-acrylic acidethyl ester

The pyridyl bromide (25 mg, 0.06 mmol) was coupled to benzeneboronicacid (7 mg, 0.05 mmol) using Method E. The residue was purified bycolumn chromatography eluting in 10% EtOAc in heptane.

Yield: 5 mg, 22%; LC/MS t_(r) 1.79 min; MS(ES+) m/z 373 (M+H).

(iii) 3-{3-[(6-Phenyl-pyridine-2-carbonyl)-amino]-phenyl}-acrylic acid(178)

The ester (5 mg, 0.001 mmol) was hydrolysed using Method G to give thetitle compound.

Yield: 5 mg, 100%; LC/MS t_(r) 1.50 min; MS(ES+) m/z 345 (M+H); HPLCPurity: 98%; ¹H NMR (400 MHz; DMSO): δ 6.55 (d, 1H), 7.43-7.65 (m, 6H),8.03 (m, 1H), 8.15 (m, 3H), 8.27 (d, 1H), 8.38 (d, 2H), 10.59 (s, 1H).

Example 11 (a) 5-Phenyl-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethoxy)-phenyl]-amide (173) (i)N-(3-Cyanomethoxy-phenyl)-acetamide

To a solution of N-(3-hydroxy-phenyl)-acetamide (5 g, 33.1 mmol) inacetone (50 ml) were added K₂CO₃ (5.49 g, 39.8 mmol) andbromo-acetonitrile (4.37 g, 36.4 mmol). The reaction mixture was heatedto 100° C. for 3 h, filtered and the acetone layer evaporated in vacuo.This residue was dissolved in EtOAc (100 ml) and washed with 1M NaOH (10ml×2). The organic layer was dried (Na₂SO₄), filtered and the solventremoved in vacuo. The crude residue was purified by columnchromatography eluting with 80% EtOAc in heptane to give the titlecompound.

Yield: 6.25 g, 99%; LC/MS t_(r) 0.92 min; MS(ES+) m/z 191 (M+H).

(ii) (3-Amino-phenoxy)-acetonitrile (172)

The acetamide (2 g, 10.5 mmol) was suspended in 1M HCl and heated to100° C. for 4.5 h. The solution was allowed to cool to room temperatureovernight, then the water was removed in vacuo to give the titlecompound as the hydrochloride salt.

Yield: 1.5 g, 97%; LC/MS t_(r) 0.66 min; MS(ES+) m/z 149 (M+H).

(iii) 5-Bromo-furan-2-carboxylic acid (3-cyanomethoxy-phenyl)-amide

5-Bromo-furan-2-carboxylic acid (325 mg, 1.70 mmol) was coupled to(3-amino-phenoxy)-acetonitrile (172) (250 mg, 1.69 mmol) using Method C.The residue was purified by column chromatography eluting with a steppedgradient of 10-30% EtOAc in heptane to give the title compound. Yield:90 mg, 16%; LC/MS t_(r) 1.34 min; MS(ES+) m/z 321, 323 (M+H).

(iv) 5-Bromo-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethoxy)-phenyl]-amide

The nitrile (100 mg, 0.31 mmol) was treated with TMSN₂ and Bu₂SnO usingMethod L, except the reaction mixture was diluted with EtOAc (2 ml) andwashed with H₂O (2×2 ml). The organic layer was dried (Na₂SO₄), filteredand the solvent removed in vacuo to give the title compound. Yield: 110mg, 97%; LC/MS t_(r) 1.17 min; MS(ES+) m/z 364, 366 (M+H).

(v) 5-Phenyl-furan-2-carboxylic acid[3-(1H-tetrazol-5-ylmethoxy)-phenyl]-amide (173)

The bromo-derivative (110 mg, 0.30 mmol) was coupled to phenylboronicacid (37 mg, 0.30 mmol) acid using Method E, except for heating to 80°C. for 20 min. After reaction, 1M HCl (3 ml) was added, and the solventswere removed in vacuo. The residue was triturated with TBME (2 ml), DCM(2 ml), and recrystallised from hot 10% EtOH in H₂O mixture to give thetitle compound.

Yield: 62 mg, 57%; LC/MS t_(r) 1.95 min; MS(ES+) m/z 362 (M+H); HPLCPurity: 95%; ¹H NMR (400 MHz, DMSO): δ 5.34 (8, 2H), 6.69 (d, 1H), 7.03(d, 1H), 7.17 (t, 1H), 7.22-7.29 (m, 3H), 7.36 (t, 2H), 7.42 (s, 1H),7.82 (s, 2H), 10.03 (s, 1H).

(b) 6-Phenyl-pyridine-2-carboxylic acid[3-(1H-tetrazol-5-ylmethoxy)-phenyl]-amide (174) (i)6-Bromo-pyridine-2-carboxylic acid (3-cyanomethoxy-phenyl)-amide

6-Bromo-pyridine-2-carboxylic acid (341 mg, 1.69 mmol) was coupled toaniline (172) (250 mg, 1.69 mmol) using Method C. The residue waspurified by column chromatography eluting with 20% EtOAc in heptane togive the title compound.

Yield: 130 mg, 23%; LC/MS t_(r) 1.43 min; MS(ES+) m/z 332, 334 (M+H).

(ii) 6-Bromo-pyridine-2-carboxylic acid[3-(1H-tetrazol-5-ylmethoxy)-phenyl]-amide

The nitrile (130 mg, 0.39 mmol) was treated with TMSN₃ and Bu₂SnO usingMethod L, except the reaction mixture was diluted with EtOAc (2 ml) andwashed with H₂O (2×2 ml). The organic layer was dried (Na₂SO₄), filteredand the solvent removed in vacuo. The residue was purified by columnchromatography eluting with 50% EtOAc in heptane followed by 5% AcOH inEtOAc to give the title compound.

Yield: 100 mg, 68%; LC/MS t_(r) 1.20 min; MS(ES+) m/z 375, 377 (M+H).

(iii) 6-Phenyl-pyridine-2-carboxylic acid[3-(1H-tetrazol-5-ylmethoxy)-phenyl]-amide (174)

The bromo-derivative (100 mg, 0.27 mmol) was coupled to phenylboronicacid (27 mg, 0.22 mmol) acid using Method E, except for heating to 80°C. for 20 min. After reaction, 1M HCl (3 ml) was added, and the aqueouslayer was extracted with EtOAc (2×2 ml). The organic layer was dried(Na₂SO₄), filtered and the solvent removed in vacuo. The residue wastriturated with TBME (2 ml) and DCM (2 ml) to give the title compound.Yield: 82 mg, 100%; LC/MS t_(r) 2.03 min; MS(ES+) m/z 373 (M+H); HPLCPurity: 93%; ¹H NMR (400 MHz, DMSO): δ 5.29 (s, 2H), 6.65 (d, 1H), 7.13(t, 1H), 7.28-7.48 (m, 4H), 7.52 (s, 1H), 7.86-7.95 (m, 2H), 8.03 (d,1H), 8.13 (d, 2H), 10.30 (s, 1H).

(c) 6-Phenyl-pyridine-2-carboxylic acid{3-[2-(1H-tetrazol-5-yl)-vinyl]phenyl}-amide (175) (i)6-Bromo-pyridine-2-carboxylic acid [3-(2-cyano-vinyl)-phenyl]-amide

6-Bromo-pyridine-2-carboxylic acid (350 mg, 1.73 mmol) was coupled toaniline (88) (250 mg, 1.74 mmol) using Method C. The residue waspurified by column chromatography eluting with 20% EtOAc in heptane togive the title compound.

Yield: 325 mg, 57%; LC/MS t_(r) 1.52 min; MS(ES+) m/z 328, 330 (M+H).

(ii) 6-Bromo-pyridine-2-carboxylic acid{3-[2-(1H-tetrazol-5-yl)-vinyl]phenyl}-amide

The nitrile (325 mg, 0.99 mmol) was reacted with TMSN₃ and Bu₂SnO usingMethod L, except the reaction mixture was diluted with EtOAc (4 ml) andwashed with H₂O (3×4 ml). The organic layer was dried (Na₂SO₄), filteredand the solvent removed in vacuo. The residue was purified by columnchromatography eluting with 50% EtOAc in heptane followed by 5% AcOH inEtOAc to give the title compound.

Yield: 334 mg, 25%; LC/MS t_(r) 1.29 min; MS(ES+) m/z 371, 373 (M+H).

(iii) 6-Phenyl-pyridine-2-carboxylic acid{3-[2-(1H-tetrazol-5-yl)-vinyl]phenyl}-amide (175)

The bromo-derivative (100 mg, 0.27 mmol) was coupled to phenylboronicacid (27 mg, 0.22 mmol) using Method E, except that the reaction washeated to 80° C. After reaction, 1M HCl (3 ml) was added, and theaqueous layer was extracted with EtOAc (2×2 ml). The organic layer wasdried (Na₂SO₄), filtered and the solvent removed in vacuo. The residuewas triturated with TBME (2 ml) and DCM (2 ml) to give the titlecompound.

Yield: 54 mg, 67%; LC/MS t_(r) 2.07 min; MS(ES+) m/z 369 (M+H); HPLCPurity: 92%; ¹H NMR (400 MHz, DMSO): δ 7.29 (d, 1H), 7.39-7.55 (m, 5H),7.67 (d, 1H), 7.92 (d, 1H), 8.02-8.12 (m, 2H), 8.03-8.23 (m, 2H),8.26-8.34 (m, 2H), 10.59 (s, 1H).

(d) 4-Fluoro-biphenyl-3-carboxylic acid{3-[2-(1H-tetrazol-5-yl)-vinyl]phenyl}-amide (176) (i)5-Bromo-N-[3-(2-cyano-vinyl)-phenyl]-2-fluoro-benzamide

5-Bromo-2-fluoro-benzoic acid (380 mg, 1.74 mmol) was coupled to aniline(88) (250 mg, 1.74 mmol) using Method C. The residue was purified bycolumn chromatography eluting with 20% EtOAc in heptane to give thetitle compound.

Yield: 353 mg, 59%; LC/MS t_(r) 1.50 min; MS(ES+) m/z 345, 347 (M+H).

(ii)5-Bromo-2-fluoro-N-{3-[2-(2H-tetrazol-5-yl)-vinyl]-phenyl}-benzamide

The nitrile (353 mg, 1.02 mmol) was treated with TMSN₃ and Bu₂SnO usingMethod L, except the reaction mixture was diluted with EtOAc (4 ml) andwashed with H₂O (3×4 ml). The organic layer was dried (Na₂SO₄), filteredand the solvent removed in vacuo. The residue was triturated with DCM (5ml) to give the title compound.

Yield: 280 mg, 71%; LC/MS t_(r) 1.32 min; MS(ES+) m/z 388, 390 (M+H).

(iii) 4-Fluoro-biphenyl-3-carboxylic acid{3-[2-(1H-tetrazol-5-yl)-vinyl]phenyl}-amide (176)

The phenyl bromide (100 mg, 0.27 mmol) was coupled to phenylboronic acid(27 mg, 0.22 mmol) using Method E, except that the reaction was heatedat 80° C. After reaction, 1M HCl (3 ml) was added, and the aqueous layerwas extracted with EtOAc (2×2 ml). The organic layer was dried (Na₂SO₄),filtered and the solvent removed in vacuo. The residue was trituratedwith TBME (2 ml) and DCM (2 ml) and further purified by preparative HPLCto give the title compound.

Yield: 15 mg, 18%; LC/MS t_(r) 2.04 min; MS(ES+) m/z 386 (M+H); HPLCPurity: 97%; ¹H NMR (400 MHz, DMSO): δ 7.39 (d, 1H), 7.49-7.69 (m, 6H),7.76 (d, 1H), 7.83-7.90 (m, 3H), 7.98-8.03 (m, 1H), 8.08 (d, 1H), 8.22(s, 1H), 10.72 (s, 1H).

Example 9 Biological Results Binding Ability to Human EP Receptors

Membranes were prepared from cells stably transfected with human EPreceptor cDNA. In brief, cells were cultured to confluency, scraped fromculture flasks, and centrifuged (800 g, 8 minutes, 4° C.). Cells weretwice washed in ice cold homogenisation buffer containing 10 mMTris-HCl,1 mM EDTA.2Na, 250 mM sucrose, 1 mM PMSF, 0.3 mM indomethacin, pH 7.4,homogenised and re-centrifuged as before. The supernatant was stored onice and pellets re-homogenised and re-spun. Supernatants were pooled andcentrifuged at 40000 g, 10 minutes, 4° C. Resultant membrane pelletswere stored at −80° C. until use.

For assay, membranes expressing human EP₄, EP₃, EP₂ or EP₁ receptorswere incubated in Millipore (MHVBN45) plates containing assay buffer,radiolabelled [³H]PGE₂ and 0.1 to 10 000 nM concentrations of compounds.Incubations were performed at suitable temperatures and for suitabletimes to allow equilibrium to be reached. Non-specific binding wasdetermined in the presence of 10 uM PGE₂. Bound and free radiolabel wasseparated by vacuum manifold filtration using appropriate wash buffers,and bound radiolabel was determined by scintillation counting.Constituents of each of the buffers are included in table 1 below.

The affinity or pK_(i) of each compound for each receptor was calculatedfrom the concentration causing 50% radioligand displacement (IC₅₀) usingthe Cheng-Prusoff equation:

${Ki} = \frac{{IC}_{50}}{1 + \left( \frac{{radioligand}\mspace{14mu} {concentration}}{{radioligand}\mspace{14mu} {KD}} \right)}$

This approach follows that set out in Kenakin, T. P., Pharmacologicanalysis of drug receptor interaction. Raven Press, New York, 2^(nd)edition.

TABLE 1 Receptor EP₁ EP₂ EP₃ EP₄ Protein/well 6.5 μg 8 μg 5 μg 5 μgFinal 3.6 nM 3 nM 2.5 nM 1 nM [³H-PGE₂] Buffer Assay 10 mM MES pH 6.0;10 mM MES 10 mM MES pH 10 mM MES 10 mM MgCl₂; 1 mM pH 6.0; 10 mM 6.0; 10mM pH 6.0; 10 mM EDTA, 3 uM MgCl₂; 1 mM MgCl₂; 1 mM MgCl₂; 1 mMIndomethacin EDTA EDTA, 100 uM EDTA, 3 uM GTP-gamma-S Indomethacin Wash10 mM MES pH 6.0; 10 mM MES 10 mM MES pH 10 mM MES 10 mM MgCl₂ pH 6.0;10 mM 6.0; 10 mM MgCl₂ pH 6.0; 1 mM MgCl₂ EDTA

Determination of Agonist Activity at Recombinant Human EP₂ ProstanoidReceptors and Antagonist Activity at EP₄ Prostanoid Receptors

HEK-293 cell clones stably transfected with human EP₂ or EP, prostanoidreceptors were cultured at 37° C. in a 5% CO₂ incubator, in 96-wellpoly-L-lysine coated plates at a density of 50,000 cells/well. Culturemedia was Minimal essential media (MEM), supplemented with 10% foetalbovine serum, 100 U/ml penicillin, 100 ng/ml streptomycin, 2.5 μg/mlfungizone, 2 mM glutamine. Cells were cultured to confluency (3-4 days)prior to use.

Culture media was removed, and confluent cells washed three times inMEM. 175 μl assay buffer (MEM containing no supplements+1 mM IBMX) wasincubated with the cells for 60 min. Cells were then stimulated by theaddition of 25 μl of PGE₂ or agonists prepared in assay buffer. Inantagonist studies, cells were pre-incubated with compounds for 30minutes prior to PGE₂-mediated stimulation

Plates were incubated for 15 min at 37° C., before termination of thereaction by the addition of 25 μl 1M HCl. The plate was then frozen at−20° C. overnight before determination of cAMP concentration.

Stimulated cAMP levels were determined by radioligand displacementbinding. In brief, plates were thawed rapidly in a waterbath, and thesamples neutralised by the addition of 25 μl 1M NaOH. 30 μl wastransferred to Millipore plates pre-coated with 0.5% Polyethylenimine(PEI). Samples were diluted by addition of 90 μl cAMP determinationbuffer (50 mM Tris, 5 mM EDTA, pH 7.0). A cAMP standard curve (10⁻¹¹M to10⁻⁵M) was constructed. 15 μl of 2 nM (final concentration) [³H] cAMP,and 15 μl of 3′5′-cAMP protein kinase (8 μg/well final concentration)prepared in cAMP determination buffer containing 0.1% BSA, were added toeach well.

Plates were incubated on ice for 2 hours, before bound and freeradiolabel were separated by vacuum filtration harvesting using theMillipore vacuum manifold, using ice cold water as the terminationbuffer.

The sealing mat was removed from the Millipore plates, and the filtersallowed to dry overnight. 50 μl Microscint 0 (Packard Bioscience) wasadded to each well, and the plate counted using the Micro-Beta Triluxtopcount ³H program.

cAMP accumulation was determined from the standard curve, and valuescalculated in pmoles cAMP/well. Antagonists affinities (pA₂ values) weredetermined assuming a elope of unity and the Gaddam-Schild equation,where pA₂=log [concentration ratio−1]−log [antagonist]. Agonistpotencies were determined from log EC₅₀ values, denoting theconcentration of agonist required to produce 50% of the agonistresponse.

Binding and functional results are presented as pK_(i) and pEC₅₀/pA₂values in table 2 below.

TABLE 2 pKi (M) pEC₅₀ EP₂ pA₂ Compound EP₂ EP₄ EP₃ (M) EP₄ (M) activity2 >5 >5 — >5 >5 EP₂ agonist/EP₄ antagonist 4 >5 >5 — >5 >5 EP₂agonist/EP₄ antagonist 10 >6 — — >6 EP₂ agonist 12 >6 — — >6 EP₂ agonist14 >6 — — >5 EP₂ agonist 16 >5 — — >5 EP₂ agonist 17 >6 — — >6 EP₂agonist 18 >6 — — >6 EP₂ agonist 19 >6 — — >5 EP₂ agonist 20 >6 — — >5EP₂ agonist 21 >6 — — >6 EP₂ agonist 22 >5 — — 23 >5 — — 24 >6 — — 25 >5— — 26 >7 >7 — >7 >6 EP₂ agonist/EP₄ antagonist 27 >7 — — >7 EP₂ agonist28 >6 — — 29 >6 — — 30 >5 — — >6 EP₂ Agonist 31 >6 >6 — >6 EP₂ agonist32 >6 >5 — 33 >5 — — 34 >6 >6 — >6 EP₂ agonist 35 >5 — — 36 >6 — — >7EP₂ agonist 37 >6 — — >6 EP₂ agonist 38 >5 — — 39 >7 — — >7 EP₂ agonist40 >6 — — >7 EP₂ agonist 41 >6 — — >6 EP₂ agonist 42 >6 — — >7 EP₂agonist 43 >5 — — 44 >6 — — >7 EP₂ agonist 45 >6 — — >7 EP₂ agonist46 >5 — — 47 >6 — — 48 >5 — — 49 >6 — — >7 EP₂ agonist 50 >5 — — 51 >6 —— >7 EP₂ agonist 52 >6 — — >7 EP₂ agonist 53 >5 — — 54 >6 — — >6 EP₂agonist 57 >5 — — >6 EP₂ Agonist 59 >5 — — 61 >7 >6 — >7 >6 EP₂agonist/EP₄ agonist 62 >6 — — >7 EP₂ agonist 63 >5 — — 66 >7 >6 — >7 >6EP₂ agonist/EP₄ agonist 68 >7 >6 — >7 >6 EP₂ agonist/EP₄ antagonist69 >7 >6 — EP₂ agonist/EP₄ antagonist 70 >7 >6 — EP₂ agonist/EP₄antagonist 71 >7 — — EP₂ agonist 72 >6 >5 — >6 >6 EP₂ agonist/EP₄antagonist 73 >5 — — 74 >5 — — >5 EP₂ agonist 75 >7 — — 81 >7 — — >7 EP₂Agonist 82 >7 — — >7 EP₂ Agonist 85 >7 — — >7 EP₂ Agonist 86 >7 — >7 EP₂Agonist 87 >7 — — >7 EP₂ Agonist 89 >7 — — >7 EP₂ Agonist 90 >7 — — >7EP₂ Agonist 92 >6 — — >7 EP₂ Agonist 93 >7 — — >7 EP₂ Agonist 94 >7 —— >7 EP₂ Agonist 95 >7 — — >7 EP₂ Agonist 96 >6 — — 97 >6 — — >6 EP₂Agonist 98 >6 — — >6 EP₂ Agonist 100 >7 >5 — >7 EP₂ Agonist 101 >7 —— >7 EP₂ Agonist 102 >7 — — 103 >7 >6 — 104 >7 — — 105 >6 — — 107 >7 —— >7 EP₂ Agonist 108 >7 — — >7 EP₂ Agonist 110 >7 — — >7 EP₂ Agonist111 >7 — — >7 EP₂ Agonist 112 >7 — — >7 EP₂ Agonist 113 >7 — — >7 EP₂Agonist 115 >7 — — >7 EP₂ Agonist 116 >7 — — >7 EP₂ Agonist 117 >6 —— >5 EP₂ Agonist 118 >6 — — >7 EP₂ Agonist 120 >5 — — >6 EP₂ Agonist121 >6 — — >6 EP₂ Agonist 122 >7 >6 — 123 >6 — — 125 >7 >5 — >7 >5 EP₂Agonist/EP₄ Antagonist 126 >7 >6 — >7 >6 EP₂ Agonist/EP₄ Antagonist127 >7 — — >7 EP₂ Agonist 128 >6 — — >7 EP₂ Agonist 129 >7 >6 — >7 >6EP₂ Agonist/EP₄ Antagonist 130 >7 >6 — >7 >6 EP₂ Agonist/EP₄ Antagonist132 >7 — — >7 EP₂ Agonist 133 >7 >6 — >7 >7 EP₂ Agonist/EP₄ Agonist134 >7 — — >7 EP₂ Agonist 135 >6 — — >6 EP₂ Agonist 137 >7 >6 — >7 EP₂Agonist 138 >7 >7 — >7 >6 EP₂ Agonist/EP₄ Agonist 140 >7 — — >7 EP₂Agonist 142 >7 — — >7 EP₂ Agonist 143 >7 — — >7 EP₂ Agonist 144 >7 >6— >7 >6 EP₂ Agonist 146 >7 — — >7 EP₂ Agonist 147 >7 — — >7 EP₂ Agonist148 >7 — — >7 EP₂ Agonist 150 >6 — — >6 EP₂ Agonist 151 >7 — — >7 EP₂Agonist 153 >7 — — >7 EP₂ Agonist 154 >7 — — >7 EP₂ Agonist 155 >7 —— >7 EP₂ Agonist 156 >7 — — >7 EP₂ Agonist 157 >7 — — >7 EP₂ Agonist158 >7 >6 — >7 EP₂ Agonist 159 >7 — — >7 EP₂ Agonist 160 >7 — — >7 EP₂Agonist 162 >7 — — >7 EP₂ Agonist 163 >7 — — >7 EP₂ Agonist 164 >6 —— >7 EP₂ Agonist 165 >7 — — >7 EP₂ Agonist 167 >7 >6 — >7 EP₂ Agonist168 >7 — — >7 EP₂ Agonist 169 >7 — — >7 EP₂ Agonist 170 >7 >6 — >7 EP₂Agonist 171 >7 — — >7 EP₂ Agonist 173 >6 — — >7 EP₂ Agonist 174 >7 >6 —175 >7 >7 — 176 >7 — — 177 >6 — — >6 EP₂ Agonist 178 >7 >7 — >7 >6 EP₂Agonist/EP₄ Agonist — denotes no appreciable affinity up to 10 μM.

1. A compound of formula (I):

or a salt, solvate and chemically protected form thereof, wherein: R⁵ isan optionally substituted C₅₋₂₀ aryl or C₄₋₂₀ alkyl group; A is selectedfrom the group consisting of:

wherein X and Y are independently selected from the group consisting of:O and CR³; S and CR³; NH and CR³; NH and N; O and N; S and N; N and S;and N and O, and where the dotted lines indicate a double bond in theappropriate location, and where Q is either N or CH; R³ is selected fromH, F, Cl and optionally substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, C₅₋₇ aryland C₅₋₇ aryl-C₁₋₄ alkyl groups; R⁴ is selected from H, F, Cl andoptionally substituted C₁₋₄ alkyl, C₁₋₄ alkoxy, C₅₋₇ aryl and C₅₋₇aryl-C₁₋₄ alkyl groups; R⁶ is selected from H, F, Cl and optionallysubstituted C₁₋₄ alkyl, C₁₋₄ alkoxy, C₅₋₇ aryl and C₅₋₇ aryl-C₁₋₄ alkylgroups; D is selected from:

B is selected from the group consisting of:

where R^(N′) is selected from H and C₁₋₄ alkyl; where one of R^(P3) andR^(P4) is —C_(m) alkylene-R² and the other of R^(P3) and R^(P4) is H, mand n can be 0 or 1, and m+n=1 or 2; and additionally when R^(P3) is—C_(m) alkylene-R², m can also be 2 or 3, and m+n=1, 2, 3 or 4, and whenR² is tetrazol-5-yl, m+n may be 0; or where one of R^(P3) and R^(P4) is—O—CH₂—R², and the other of R^(P3) and R^(P4) is H, n is 0; R^(N) is Hor optionally substituted C₁₋₄ alkyl; R² is either: (i) —CO₂H (carboxy);(ii) —CONH₂; (iii) —CH₂—OH (methoxy); or (iv) tetrazol-5-yl.
 2. Acompound according to claim 1, wherein R⁵ is phenyl optionallysubstituted with one or more substituents independently selected from:C₁₋₄ alkyl, C₁₋₄ alkoxy, C₅₋₆ aryl, halo, acyl, amino, alkoxylene.
 3. Acompound according to claim 1, wherein R⁵ is a C₄₋₁₀ alkyl group.
 4. Acompound according to claim 1, wherein A is selected from:


5. A compound according to claim 1, wherein A is a five membered ring,and R³ (if present) and R⁴ are independently selected from H andoptionally substituted C₁₋₄ alkyl.
 6. A compound according to claim 1,wherein A is a six-membered ring, and either: (i) R³, R⁴ and R⁶ (ifpresent) are H; or (ii) one of R³, R⁴ and R⁶ (if present) are Cl or F.7. A compound according to claim 1, wherein D is:


8. A compound according to claim 7, wherein R^(N) is H.
 9. A compoundaccording to claim 1, wherein B is:


10. A compound according to claim 1, wherein R² is carboxy ortetrazoly-5-yl.
 11. A compound according to claim 10, wherein R² iscarboxy.
 12. A compound according to claim 1, wherein R^(P4) is H, andR^(P3) is —CH═CH—R².
 13. A compound according to claim 1, wherein R^(P3)is —O—CH₂—R².
 14. A pharmaceutical composition comprising a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereoftogether with a pharmaceutically acceptable carrier or diluent.
 15. Amethod of treating a condition which can be alleviated by agonism of anEP₂ receptor, which method comprises administering to a patient in needof treatment an effective amount of a compound according to claim 1, ora pharmaceutically acceptable salt thereof.
 16. A method of treating acondition comprising administering to a patient in need of treatment aneffective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein the condition isselected from dysmenorrhoea, pre-term labour, glaucoma, ocularhypertension, immune disorders, inflammatory disorders, osteoporosis,asthma, chronic obstructive pulmonary disease, allergy, bone disease,fracture repair, male sexual dysfunction, female sexual dysfunction,infertility, periodontal disease, gastric ulcer, renal disease andpsoriasis, psoriatic arthritis, dermatitis, rheumatoid arthritis,transplant rejection, inflammatory bowel disease, systemic lupuserythematosus, vasculitis, acute respiratory distress syndrome,pulmonary fibrosis, cystic fibrosis, Graves' disease, scleroderma,multiple sclerosis, and type I diabetes.
 17. The method of treating acondition according to claim 16 wherein the condition is selected fromdysmenorrhoea, pre-term labour, glaucoma, ocular hypertension, immunedisorders, inflammatory disorders, osteoporosis, asthma, chronicobstructive pulmonary disease, allergy, bone disease, fracture repair,male sexual dysfunction, female sexual dysfunction, infertility,periodontal disease, gastric ulcer, renal disease and psoriasis.
 18. Themethod according to claim 16, wherein the condition is glaucoma orocular hypertension.